Systems Pharmacology as a tool for future therapy development: a feasibility ...Guide to PHARMACOLOGY
This study explores using a systems pharmacology approach to analyze the mevalonate branch of the cholesterol biosynthesis pathway. Kinetic parameters and inhibitors of the pathway enzymes were identified from literature and databases. An ordinary differential equation model of the pathway was built and used to predict the optimal drug combination that would suppress production of the cholesterol precursor squalene while maintaining production of geranylgeranyl-PP. The predicted multi-drug approach required a lower total dose than treatment with the statin drug rosuvastatin alone. However, the study found that incomplete and ambiguous pathway data as well as errors in databases currently limit full potential of systems pharmacology approaches.
Drug-to-protein mappings in the Guide to PHARMACOLOGY: Utility as a target va...Guide to PHARMACOLOGY
The Guide to Pharmacology database (GtoPdb) provides expertly curated information on drug-protein interactions and targets of approved and investigational drugs. It currently includes data on interactions between over 1400 protein targets and 7700 ligands derived from over 5000 literature references. The database covers major target classes and provides a useful resource for target validation and drug discovery. Future plans include regular updates with new target and drug data as well as potential specialty sub-portals within the database.
Study on multi-target mechanism of Radix et Rhizoma Rhei (Dahuang) and Semen ...LucyPi1
Abstract Objective: To explore the mechanism of action of Radix et Rhizoma Rhei (Dahuang) (RERR) and Semen Persicae (Taoren) (SP) on adhesive intestinal obstruction (AIO). Methods: The main targets of the active ingredients of RERR and SP were filtered based on the traditional Chinese medicine system pharmacology analysis platform. Cytoscape 3.2.1 was applied to build the ingredient-target network of RERR and SP for AIO. Results: Fifteen active components were predicted from the RERR and SP herb pair, such as aloe-emodin, catechin, rhein, gibberellin (GA) 119, GA120 and GA121. These components were applied to 59 targets mainly involved in many biological processes such as signal transduction, anti-apoptosis, and inflammatory response involved in activating the immune effect. Conclusion: This study proposes the system pharmacology method and identifies the potent combination therapeutic mechanism of RERR and SP for AIO. This strategy will provide a new insight to the study of herb combinations.
Poster titled "The imperative of small, high quality data for underpinning big data: the IUPHAR/BPS Guide to PHARMACOLOGY". Presented by Dr. Christopher Southan, at the British Society of Pharmacology, Institute for Translational Medicine & Therapeutics (ITMAT) Meeting, Edinburgh, March 2017, ‘Big Data & the Development of New Medicines’.
This study aimed to identify existing drug therapies that could potentially be repurposed to treat gastric cancer. Differentially expressed genes from microarray analyses of gastric cancer tissue samples were submitted to the Connectivity Map database to identify candidate drugs that could reverse disease signatures. Vorinostat and trichostatin A, both histone deacetylase inhibitors, were predicted as potential therapies based on their expression profiles opposing those of gastric cancer tumors. Future work will integrate biological pathway knowledge to link predicted drugs to relevant pathways.
Discovery PBPK: How to estimate the expected accuracy of ISIVB and IVIVB for ...Simulations Plus, Inc.
This slideshow was presented at the 2018 - 6th Asia Pacific Regional ISSX meeting in Hangzhou, China. Chief Scientist Michael Bolger, explains how Simulations Plus’ PBPK modeling and simulation software can be used successfully in the lead optimization phase of drug discovery.
Poster presented at the Elixir All-Hands Meeting in Lisbon, June 2019. Gives a broad summary of Guide to Pharmacology activities in the last year. Emphasising new tools and our extension into malaria pharmacology.
Analysing curated protein targets: Partitioning the drugged and the druggable Chris Southan
The document summarizes the Guide to Pharmacology (GtoPdb) database, which curates ligand-protein interaction data from the literature. The database captures interactions between 1460 proteins and 7733 ligands from over 5000 references. It facilitates analysis of drug targets and comparison of druggable targets with compounds tested in vivo. The document then analyzes the genome ontology classifications of targets in the database compared to all human proteins, showing enrichment of receptors, enzymes and transporters in druggable targets. It also provides breakdowns of target characteristics like pathway membership and transmembrane domains. Finally, it uses Venn diagrams to compare targets of approved drugs with high vs. low affinity ligands, showing high-affinity drugs are biased toward receptors.
Systems Pharmacology as a tool for future therapy development: a feasibility ...Guide to PHARMACOLOGY
This study explores using a systems pharmacology approach to analyze the mevalonate branch of the cholesterol biosynthesis pathway. Kinetic parameters and inhibitors of the pathway enzymes were identified from literature and databases. An ordinary differential equation model of the pathway was built and used to predict the optimal drug combination that would suppress production of the cholesterol precursor squalene while maintaining production of geranylgeranyl-PP. The predicted multi-drug approach required a lower total dose than treatment with the statin drug rosuvastatin alone. However, the study found that incomplete and ambiguous pathway data as well as errors in databases currently limit full potential of systems pharmacology approaches.
Drug-to-protein mappings in the Guide to PHARMACOLOGY: Utility as a target va...Guide to PHARMACOLOGY
The Guide to Pharmacology database (GtoPdb) provides expertly curated information on drug-protein interactions and targets of approved and investigational drugs. It currently includes data on interactions between over 1400 protein targets and 7700 ligands derived from over 5000 literature references. The database covers major target classes and provides a useful resource for target validation and drug discovery. Future plans include regular updates with new target and drug data as well as potential specialty sub-portals within the database.
Study on multi-target mechanism of Radix et Rhizoma Rhei (Dahuang) and Semen ...LucyPi1
Abstract Objective: To explore the mechanism of action of Radix et Rhizoma Rhei (Dahuang) (RERR) and Semen Persicae (Taoren) (SP) on adhesive intestinal obstruction (AIO). Methods: The main targets of the active ingredients of RERR and SP were filtered based on the traditional Chinese medicine system pharmacology analysis platform. Cytoscape 3.2.1 was applied to build the ingredient-target network of RERR and SP for AIO. Results: Fifteen active components were predicted from the RERR and SP herb pair, such as aloe-emodin, catechin, rhein, gibberellin (GA) 119, GA120 and GA121. These components were applied to 59 targets mainly involved in many biological processes such as signal transduction, anti-apoptosis, and inflammatory response involved in activating the immune effect. Conclusion: This study proposes the system pharmacology method and identifies the potent combination therapeutic mechanism of RERR and SP for AIO. This strategy will provide a new insight to the study of herb combinations.
Poster titled "The imperative of small, high quality data for underpinning big data: the IUPHAR/BPS Guide to PHARMACOLOGY". Presented by Dr. Christopher Southan, at the British Society of Pharmacology, Institute for Translational Medicine & Therapeutics (ITMAT) Meeting, Edinburgh, March 2017, ‘Big Data & the Development of New Medicines’.
This study aimed to identify existing drug therapies that could potentially be repurposed to treat gastric cancer. Differentially expressed genes from microarray analyses of gastric cancer tissue samples were submitted to the Connectivity Map database to identify candidate drugs that could reverse disease signatures. Vorinostat and trichostatin A, both histone deacetylase inhibitors, were predicted as potential therapies based on their expression profiles opposing those of gastric cancer tumors. Future work will integrate biological pathway knowledge to link predicted drugs to relevant pathways.
Discovery PBPK: How to estimate the expected accuracy of ISIVB and IVIVB for ...Simulations Plus, Inc.
This slideshow was presented at the 2018 - 6th Asia Pacific Regional ISSX meeting in Hangzhou, China. Chief Scientist Michael Bolger, explains how Simulations Plus’ PBPK modeling and simulation software can be used successfully in the lead optimization phase of drug discovery.
Poster presented at the Elixir All-Hands Meeting in Lisbon, June 2019. Gives a broad summary of Guide to Pharmacology activities in the last year. Emphasising new tools and our extension into malaria pharmacology.
Analysing curated protein targets: Partitioning the drugged and the druggable Chris Southan
The document summarizes the Guide to Pharmacology (GtoPdb) database, which curates ligand-protein interaction data from the literature. The database captures interactions between 1460 proteins and 7733 ligands from over 5000 references. It facilitates analysis of drug targets and comparison of druggable targets with compounds tested in vivo. The document then analyzes the genome ontology classifications of targets in the database compared to all human proteins, showing enrichment of receptors, enzymes and transporters in druggable targets. It also provides breakdowns of target characteristics like pathway membership and transmembrane domains. Finally, it uses Venn diagrams to compare targets of approved drugs with high vs. low affinity ligands, showing high-affinity drugs are biased toward receptors.
PAMAM/5-fluorouracil drug conjugate for targeting E6 and E7 oncoproteins in c...Arun kumar
In the present study, poly(amidoamine)/5-fluorouracil (PAMAM/5-FU) was prepared and used as
a conjugate system for delivering drugs to target E6 and E7 oncoproteins, which are predominant in
cervical cancers. Specifically, molecular docking analysis was used to investigate the interaction
between the PAMAM/5-FU and E6/E7 oncoproteins, which showed that the PAMAM/5-FU conjugate
had a higher affinity for the oncoprotein than for 5-FU. Different generations of PAMAM dendrimers
(0.5G, 1.0G, 1.5G, 2.0G, and 2.5G) were synthesized, characterized and tested as drug carriers for 5-
FU. The PAMAM and PAMAM/5-FU drug conjugate showed less toxicity over COS-7 and HeLa cell
lines. Laser confocal imaging and western blotting for tumor suppressor proteins pRb and p53 were
used to confirm the interaction of PAMAM/5-FU with E6/E7 oncoproteins. Hematological analysis of
PAMAM/5-FU using BALB/c female mice with cervical cancer confirmed the less toxic nature of this
material. Based on these results, the developed PAMAM/5-FU conjugate is a potential candidate for
the treatment of cervical cancer.
An Introduction to:In Vitro-In VivoExtrapolation (IVIVE)mjamei
This document provides an overview of in vitro-in vivo extrapolation (IVIVE) and introduces the company Simcyp and its work in mechanistic modeling of pharmacokinetics and pharmacodynamics. It discusses how Simcyp uses physiological and drug data along with population variability to develop mechanistic models for predicting drug absorption, distribution, metabolism, and excretion in virtual populations.
Cheminformatics is an interdisciplinary field that combines chemistry, biology, physics, mathematics, and computer science to manage chemical data and information. It plays a key role in processing the enormous amount of chemical data produced by chemists, maintaining databases, and extracting knowledge from data to model relationships between compound structure and biological activity. Cheminformatics has three major aspects: information acquisition, information management, and information use. It complements bioinformatics by addressing molecular processes like protein structure and function.
Allometric scaling is a method used to estimate drug doses and pharmacokinetic parameters between species. It is based on the principle that physiological processes like metabolism scale non-linearly with body weight. PK parameters like clearance and volume of distribution are collected from multiple species, converted to logarithmic values, and regression analysis is performed to derive allometric equations. This method is preferred over simple linear scaling as it accounts for size-dependent differences between species and avoids under- or overdosing. However, species differences in drug targets, metabolism and excretion need consideration for accurate translation of doses.
Mass Spectrometry-Based Proteomics Quantification: iTRAQ Creative Proteomics
This document discusses iTRAQ (isobaric tag for relative and absolute quantitation), a method for determining the amount of proteins from different sources in a single experiment. It describes the basic structure of iTRAQ reagents, which consist of a unique reporter group, peptide reactive group, and neutral balance group. The principle and workflow of iTRAQ is explained, involving labeling samples with iTRAQ tags, combining samples, performing MS/MS for identification and quantitation. Factors affecting iTRAQ results and its advantages/disadvantages are briefly covered. An example application of iTRAQ to identify tyrosine phosphorylation sites is provided.
Reference scaled average bioequivalence analysisCertara
About 20% of generic drugs appear to be highly variable. Because of their highly variability, studies designed to show the bioequivalence of these drugs may require enrolling a large number of subjects. The Reference Scaled Average Bioequivalance (RSABE) approach helps show bioequivalence for highly variable drugs using a typical sample size in order to save money and minimize patient exposure. RSABE can be performed in Phoenix WinNonlni using reusable templates projects and workflows for both the EMA and FDA approaches.
Unveiling the role of network and systems biology in drug discoverychengcheng zhou
This document reviews recent advances in network and systems biology applied to human health and drug discovery. It discusses how these approaches consider biological targets in their physiological context without losing molecular details. Network biology will be central to developing polypharmacology strategies for complex multi-factorial diseases by altering entire pathways rather than single proteins. Predictive toxicology and drug repurposing are areas where network and systems biology strategies could have an immediate impact on drug discovery.
This document summarizes a seminar on computational methods for drug disposition. It discusses two approaches to modeling drug disposition: qualitative and quantitative. The quantitative approach uses pharmacophore modeling and docking to study drug interactions, while the qualitative approach uses QSAR and QSPR to correlate molecular descriptors with ADMET properties. The document also reviews the key processes of drug disposition: absorption, distribution, metabolism, and excretion. It provides examples of two research articles, one on the placental disposition of the immunosuppressant tacrolimus, and another on the pharmacokinetics of miltefosine in mice and hamsters infected with Leishmania.
The document discusses targeted drug delivery approaches. It defines targeted delivery as delivering medication to tissues of interest to reduce side effects. Various approaches are described, including passive targeting using carriers that accumulate in tissues, active targeting using surface modifications like antibodies, and physical targeting using environmental characteristics like pH. The strategies aim to improve drug efficacy and safety by selectively delivering therapeutic agents to specific sites in the body.
QSAR Studies of the Inhibitory Activity of a Series of Substituted Indole and...inventionjournals
HF method, with the basis set 6-31G (d) was employed to calculate quantum some chemical descriptors of 37 substituted Indole. The best descriptors were selected to establish the quantitative structure activity relationship (QSAR) of the inhibitory activity against isoprenylcysteine carboxyl methyltransferase (Icmt), by principal components analysis (PCA), to a multiple regression analysis (MLR), to a nonlinear regression (RNLM) and to an artificial neural network (ANN). We accordingly propose a quantitative model and we interpret the activity of the compounds relying on the multivariate statistical analysis. This study shows that the MLR and have served to predict activity, but when compared with the results given by the ANN model. We concluded that the predictions achieved by this latter is more effective and much better than other models. The statistical results indicate that the model is statistically significant and shows very good stability towards data variation in the validation method. The contribution of each descriptor to the structure-activity relationship is evaluated.
GtoPdb: A resource for cell-based perturbogensChris Southan
Poster for ELRIG, Möndal, 11/12 May 2017.
This poster will also be presented at BioITWorld, Boston, May 23-25
A resource for the selection and interpretation of cell-based perturbogens: the IUPHAR/BPS Guide to PHARMACOLOGY
Christopher Southan, Elena Faccenda, Joanna L. Sharman, Adam J. Pawson, Simon D. Harding, Jamie A Davies,
Translational research requires the integration of the in vitro molecular mechanisms of action (mmoa) of small molecules, cell-based screening studies, animal models and eventual clinical trials. The International Union of Pharmacology (IUPHAR)/British Pharmacology Society (BPS) database, GtoPdb http://www.guidetopharmacology.org/ provides expert-annotated molecular interactions between endogenous receptor ligands, probes, lead compounds, clinical drugs and their protein targets. It thus provides a core set of quantitative pharmacological relationships that can be interrogated for many purposes, including those running cell-based screens, not only during result interpretation but also to identify key compounds for scoping and consolidation experiments. As described in [1] GtoPdb is populated by records extracted from pharmacology and medicinal chemistry journals, and released quarterly. Quality is ensured by curatorial stringency and our unique model of content selection based on recommendations from IUPHAR target class subcommittees of international experts collaborating with the in-house curators. The database now has over 14 000 binding values (mainly IC50, Ki or Kd) between 8000 ligands and 15000 human proteins (mainly primary but also secondary off-target interactions) representing a 7% druggable proteome. Our coverage is complementary to other sources. For example the 6565 structures we recently submitted to PubChem as CIDs, 5206 were not in DrugBank and 1535 not in ChEMBL. This includes recommended tool compounds with relatively defined mmoa (including 110 from the Structural Genomics Consortium Probe Portal). We also have 75% overlap with vendors for procurement and 80% with patent extractions that in many cases allow mapping to SAR data sets from first-filings (some of which we point to). In a cell screening context 1254 of our targets intersect with proteins in the Reactome pathway database. This is one way to select chemical peturbation points that could be detected by assay readouts. From Nov 2015 we have been funded by the Wellcome Trust to extend into immunopharmacology (within the existing database schema) that is now driving overall GtoPdb content expansion. Parties engaged in cell based assays using or could use compounds we have are encouraged to use GtoPdb, contact us for queries, possible analogue expansions and/or alert us to prospective new content. [1] Southan C et. al. (2016) Nucleic Acids Res. 44(D1):D1054-68, PMID: 26464438
It encloses a brief description of flux balance analysis tools, flux measuring software, methods, advantages and comparable applications to the other software's and analysis techniques and discussion so on steady - constraint based analysis modelling, reconstruction of metabolic pathways and different constraints. etc.
In vitro screening for evaluation of drugs ADMET propertiesdilip kumar tampula
The document discusses pre-clinical in vitro screening techniques used to evaluate drugs' absorption, distribution, metabolism, excretion and toxicity (ADMET) properties early in the drug discovery process. It describes assays for various ADMET properties including partition coefficient, aqueous solubility, metabolic stability, plasma protein binding, and toxicity. The assays allow rapid evaluation of compounds with low amounts of material and help identify those with favorable pharmacokinetic and safety profiles to progress in development. The goal is to incorporate ADMET screening earlier to simultaneously optimize all drug properties.
If you want to know more, please visit https://www.creative-proteomics.com/s...
Stable isotope labeling using amino acids in cell culture (SILAC) is a powerful method based on mass spectrometry that identifies and quantifies relative differential changes in protein abundance. First used in quantitative proteomics in 2002, it provides accurate relative quantification without any chemical derivatization or manipulation.
This document discusses metabolic pathways and networks. It describes genome-scale metabolic models that include all known metabolic genes and reactions. These models can integrate omics data in a biologically meaningful way and be used to map genes, contextualize pathological states, and simulate drug effects. The document presents an application of metabolic network analysis to interpret urine metabolomics data from ADHD and autism patients to gain insights into disrupted tryptophan metabolism.
This document provides an overview of pharmacophore mapping and pharmacophore-based screening. It defines a pharmacophore as the pattern of molecular features responsible for a drug's biological activity. The key steps in pharmacophore modeling are identifying common binding elements in active compounds, generating potential ligand conformations, and determining the 3D relationships between pharmacophore elements. Pharmacophore models can be generated manually based on known active ligands or automatically using software. Receptor-based pharmacophore generation uses the 3D structure of the target protein to identify favorable binding sites. Overall, pharmacophore mapping is used in computer-aided drug design to identify novel ligands that interact with the same biological target.
Metabolic network mapping for metabolomicsDinesh Barupal
We present a novel approach to integrate biochemical pathway and chemical relationships to map all detected metabolites in network graphs (MetaMapp) using KEGG reactant pair database, Tanimoto chemical and NIST mass spectral similarity scores. In fetal and maternal lungs, and in maternal blood plasma from pregnant rats exposed to environmental tobacco smoke (ETS), 459 unique metabolites comprising 179 structurally identified compounds were detected by gas chromatography time of flight mass spectrometry (GC-TOF MS) and BinBase data processing. MetaMapp graphs in Cytoscape showed much clearer metabolic modularity and complete content visualization compared to conventional biochemical mapping approaches. Cytoscape visualization of differential statistics results using these graphs showed that overall, fetal lung metabolism was more impaired than lungs and blood metabolism in dams. Fetuses from ETS-exposed dams expressed lower lipid and nucleotide levels and higher amounts of energy metabolism intermediates than control animals, indicating lower biosynthetic rates of metabolites for cell division, structural proteins and lipids that are critical for in lung development.
MetaMapp graphs efficiently visualizes mass spectrometry based metabolomics datasets as network graphs in Cytoscape, and highlights metabolic alterations that can be associated with higher rate of pulmonary diseases and infections in children prenatally exposed to ETS. The MetaMapp scripts can be accessed at http://metamapp.fiehnlab.ucdavis.edu.
A New Platform for Combining the ‘Bottom-Up’ PBPK Paradigm and POPPK Data Ana...mjamei
The document discusses combining bottom-up physiologically-based pharmacokinetic (PBPK) modeling with top-down population pharmacokinetic (POPPK) data analysis. It describes current and previous Simcyp team members and grants received. It then contrasts top-down and bottom-up approaches, highlighting how the bottom-up approach can incorporate more physiological covariates compared to the empirical top-down approach. The document outlines Simcyp's parameter estimation module, which allows fitting simulations to clinical data to estimate population and drug parameters.
techniques used in Metabolite profiling of bryophytes pptUnnatiChopra1
The document discusses techniques used in metabolite profiling of bryophytes. It begins with an introduction to bryophytes and metabolite profiling. It then describes several techniques used for metabolite profiling including gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS), capillary electrophoresis-mass spectrometry (CE-MS), and nuclear magnetic resonance spectroscopy (NMR). Specific examples of how these techniques have been applied to study metabolite profiling in bryophytes are also provided. The document concludes with recommendations for future research and a summary of the importance of metabolite profiling.
Rushikesh Shinde presented on computational modeling of drug disposition at Alard College of Pharmacy. The presentation discussed how modeling absorption, solubility, and intestinal permeation can help predict drug behavior in the body. Historically, drug candidates often failed in late-stage clinical trials due to issues related to metabolism, excretion, and toxicity, which computational modeling seeks to evaluate earlier in the drug development process. The presentation covered techniques like quantitative structure-activity relationship analysis and pharmacokinetic modeling to computationally simulate drug properties.
Exploiting Edinburgh's Guide to PHARMACOLOGY database as a source of protein ...Chris Southan
Presented by Jamie Davies at the SULSA Synthetic Biology Meeting, Edinburgh, 10 June 2014
http://www.eventbrite.co.uk/e/sulsa-synthetic-biology-meeting-registration-11251454403?aff=eorg
Abstract: Synthetic creation of new biological systems typically incorporates pathways and signaling modules from known protein building blocks. Testing the models underpinning the synthetic engineering thus needs the experimental manipulation of individual proteins, for example, ablating a specific enzyme activity via RNAi, SNP mutation, or knockout. However, the option of small-molecule inhibition as the system perturbation has the advantages of 1) rapid onset 2) dose-response 3) analog testing for structure-activity relationships, 4) exploring mixtures for combinatorial effects 5) pulsing and reversal by wash-out. 6) accurate measurements of added substances and 7) a vast precedent of published results in natural systems from medicinal chemistry, pharmacology, and chemical biology. For the synthetic biologists the GToPdb1 can thus be considered as compendium of the latter. It encompasses an interaction matrix between ~4000 small molecules and ~1000 human proteins with a focus on drugs, clinical candidates, research compounds and peptide ligands These not only have ~ 10,000 mapped binding constants but also the spectrum of documented modulation extends across enzymes, receptors, channels and transporters. It thus becomes an increasingly plausible option to choose a “Lego protein” from GToPdb as a synthetic system component that can have experimentally useable activity probes available from chemical vendors. Even if it does not currently have a suitable target-probe pair, as knowledge base (and expertise resource via the curation team who populate it) GToPdb is an ideal starting point from which to walk out to wider chemogenomic spaces. For example, while an approved drug and its target might seem a logical choice, analogs from the lead series or different chemotypes from which the drug was optimized, or even failed in development, can have superior probe-like properties for in vitro experiments (e.g. be more potent, specific and soluble). The GToPdb facilitates access to such compound data via curated papers and patents.
References
1. Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SP, Buneman OP, Davenport AP, McGrath JC, Peters JA, Southan C, Spedding M, Yu W, Harmar AJ; NC-IUPHAR. The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands. Nucleic Acids Res. 2014 Jan 1;42(1)
This document discusses genomics and proteomics based drug discovery. It explains that genomics involves sequencing genomes to understand gene functions and interactions, while proteomics studies protein expression and interactions. The document outlines how structural bioinformatics and techniques like protein-ligand docking can help in drug target identification and rational drug design. It also discusses how proteomics can aid in various stages of drug discovery like target identification and validation.
PAMAM/5-fluorouracil drug conjugate for targeting E6 and E7 oncoproteins in c...Arun kumar
In the present study, poly(amidoamine)/5-fluorouracil (PAMAM/5-FU) was prepared and used as
a conjugate system for delivering drugs to target E6 and E7 oncoproteins, which are predominant in
cervical cancers. Specifically, molecular docking analysis was used to investigate the interaction
between the PAMAM/5-FU and E6/E7 oncoproteins, which showed that the PAMAM/5-FU conjugate
had a higher affinity for the oncoprotein than for 5-FU. Different generations of PAMAM dendrimers
(0.5G, 1.0G, 1.5G, 2.0G, and 2.5G) were synthesized, characterized and tested as drug carriers for 5-
FU. The PAMAM and PAMAM/5-FU drug conjugate showed less toxicity over COS-7 and HeLa cell
lines. Laser confocal imaging and western blotting for tumor suppressor proteins pRb and p53 were
used to confirm the interaction of PAMAM/5-FU with E6/E7 oncoproteins. Hematological analysis of
PAMAM/5-FU using BALB/c female mice with cervical cancer confirmed the less toxic nature of this
material. Based on these results, the developed PAMAM/5-FU conjugate is a potential candidate for
the treatment of cervical cancer.
An Introduction to:In Vitro-In VivoExtrapolation (IVIVE)mjamei
This document provides an overview of in vitro-in vivo extrapolation (IVIVE) and introduces the company Simcyp and its work in mechanistic modeling of pharmacokinetics and pharmacodynamics. It discusses how Simcyp uses physiological and drug data along with population variability to develop mechanistic models for predicting drug absorption, distribution, metabolism, and excretion in virtual populations.
Cheminformatics is an interdisciplinary field that combines chemistry, biology, physics, mathematics, and computer science to manage chemical data and information. It plays a key role in processing the enormous amount of chemical data produced by chemists, maintaining databases, and extracting knowledge from data to model relationships between compound structure and biological activity. Cheminformatics has three major aspects: information acquisition, information management, and information use. It complements bioinformatics by addressing molecular processes like protein structure and function.
Allometric scaling is a method used to estimate drug doses and pharmacokinetic parameters between species. It is based on the principle that physiological processes like metabolism scale non-linearly with body weight. PK parameters like clearance and volume of distribution are collected from multiple species, converted to logarithmic values, and regression analysis is performed to derive allometric equations. This method is preferred over simple linear scaling as it accounts for size-dependent differences between species and avoids under- or overdosing. However, species differences in drug targets, metabolism and excretion need consideration for accurate translation of doses.
Mass Spectrometry-Based Proteomics Quantification: iTRAQ Creative Proteomics
This document discusses iTRAQ (isobaric tag for relative and absolute quantitation), a method for determining the amount of proteins from different sources in a single experiment. It describes the basic structure of iTRAQ reagents, which consist of a unique reporter group, peptide reactive group, and neutral balance group. The principle and workflow of iTRAQ is explained, involving labeling samples with iTRAQ tags, combining samples, performing MS/MS for identification and quantitation. Factors affecting iTRAQ results and its advantages/disadvantages are briefly covered. An example application of iTRAQ to identify tyrosine phosphorylation sites is provided.
Reference scaled average bioequivalence analysisCertara
About 20% of generic drugs appear to be highly variable. Because of their highly variability, studies designed to show the bioequivalence of these drugs may require enrolling a large number of subjects. The Reference Scaled Average Bioequivalance (RSABE) approach helps show bioequivalence for highly variable drugs using a typical sample size in order to save money and minimize patient exposure. RSABE can be performed in Phoenix WinNonlni using reusable templates projects and workflows for both the EMA and FDA approaches.
Unveiling the role of network and systems biology in drug discoverychengcheng zhou
This document reviews recent advances in network and systems biology applied to human health and drug discovery. It discusses how these approaches consider biological targets in their physiological context without losing molecular details. Network biology will be central to developing polypharmacology strategies for complex multi-factorial diseases by altering entire pathways rather than single proteins. Predictive toxicology and drug repurposing are areas where network and systems biology strategies could have an immediate impact on drug discovery.
This document summarizes a seminar on computational methods for drug disposition. It discusses two approaches to modeling drug disposition: qualitative and quantitative. The quantitative approach uses pharmacophore modeling and docking to study drug interactions, while the qualitative approach uses QSAR and QSPR to correlate molecular descriptors with ADMET properties. The document also reviews the key processes of drug disposition: absorption, distribution, metabolism, and excretion. It provides examples of two research articles, one on the placental disposition of the immunosuppressant tacrolimus, and another on the pharmacokinetics of miltefosine in mice and hamsters infected with Leishmania.
The document discusses targeted drug delivery approaches. It defines targeted delivery as delivering medication to tissues of interest to reduce side effects. Various approaches are described, including passive targeting using carriers that accumulate in tissues, active targeting using surface modifications like antibodies, and physical targeting using environmental characteristics like pH. The strategies aim to improve drug efficacy and safety by selectively delivering therapeutic agents to specific sites in the body.
QSAR Studies of the Inhibitory Activity of a Series of Substituted Indole and...inventionjournals
HF method, with the basis set 6-31G (d) was employed to calculate quantum some chemical descriptors of 37 substituted Indole. The best descriptors were selected to establish the quantitative structure activity relationship (QSAR) of the inhibitory activity against isoprenylcysteine carboxyl methyltransferase (Icmt), by principal components analysis (PCA), to a multiple regression analysis (MLR), to a nonlinear regression (RNLM) and to an artificial neural network (ANN). We accordingly propose a quantitative model and we interpret the activity of the compounds relying on the multivariate statistical analysis. This study shows that the MLR and have served to predict activity, but when compared with the results given by the ANN model. We concluded that the predictions achieved by this latter is more effective and much better than other models. The statistical results indicate that the model is statistically significant and shows very good stability towards data variation in the validation method. The contribution of each descriptor to the structure-activity relationship is evaluated.
GtoPdb: A resource for cell-based perturbogensChris Southan
Poster for ELRIG, Möndal, 11/12 May 2017.
This poster will also be presented at BioITWorld, Boston, May 23-25
A resource for the selection and interpretation of cell-based perturbogens: the IUPHAR/BPS Guide to PHARMACOLOGY
Christopher Southan, Elena Faccenda, Joanna L. Sharman, Adam J. Pawson, Simon D. Harding, Jamie A Davies,
Translational research requires the integration of the in vitro molecular mechanisms of action (mmoa) of small molecules, cell-based screening studies, animal models and eventual clinical trials. The International Union of Pharmacology (IUPHAR)/British Pharmacology Society (BPS) database, GtoPdb http://www.guidetopharmacology.org/ provides expert-annotated molecular interactions between endogenous receptor ligands, probes, lead compounds, clinical drugs and their protein targets. It thus provides a core set of quantitative pharmacological relationships that can be interrogated for many purposes, including those running cell-based screens, not only during result interpretation but also to identify key compounds for scoping and consolidation experiments. As described in [1] GtoPdb is populated by records extracted from pharmacology and medicinal chemistry journals, and released quarterly. Quality is ensured by curatorial stringency and our unique model of content selection based on recommendations from IUPHAR target class subcommittees of international experts collaborating with the in-house curators. The database now has over 14 000 binding values (mainly IC50, Ki or Kd) between 8000 ligands and 15000 human proteins (mainly primary but also secondary off-target interactions) representing a 7% druggable proteome. Our coverage is complementary to other sources. For example the 6565 structures we recently submitted to PubChem as CIDs, 5206 were not in DrugBank and 1535 not in ChEMBL. This includes recommended tool compounds with relatively defined mmoa (including 110 from the Structural Genomics Consortium Probe Portal). We also have 75% overlap with vendors for procurement and 80% with patent extractions that in many cases allow mapping to SAR data sets from first-filings (some of which we point to). In a cell screening context 1254 of our targets intersect with proteins in the Reactome pathway database. This is one way to select chemical peturbation points that could be detected by assay readouts. From Nov 2015 we have been funded by the Wellcome Trust to extend into immunopharmacology (within the existing database schema) that is now driving overall GtoPdb content expansion. Parties engaged in cell based assays using or could use compounds we have are encouraged to use GtoPdb, contact us for queries, possible analogue expansions and/or alert us to prospective new content. [1] Southan C et. al. (2016) Nucleic Acids Res. 44(D1):D1054-68, PMID: 26464438
It encloses a brief description of flux balance analysis tools, flux measuring software, methods, advantages and comparable applications to the other software's and analysis techniques and discussion so on steady - constraint based analysis modelling, reconstruction of metabolic pathways and different constraints. etc.
In vitro screening for evaluation of drugs ADMET propertiesdilip kumar tampula
The document discusses pre-clinical in vitro screening techniques used to evaluate drugs' absorption, distribution, metabolism, excretion and toxicity (ADMET) properties early in the drug discovery process. It describes assays for various ADMET properties including partition coefficient, aqueous solubility, metabolic stability, plasma protein binding, and toxicity. The assays allow rapid evaluation of compounds with low amounts of material and help identify those with favorable pharmacokinetic and safety profiles to progress in development. The goal is to incorporate ADMET screening earlier to simultaneously optimize all drug properties.
If you want to know more, please visit https://www.creative-proteomics.com/s...
Stable isotope labeling using amino acids in cell culture (SILAC) is a powerful method based on mass spectrometry that identifies and quantifies relative differential changes in protein abundance. First used in quantitative proteomics in 2002, it provides accurate relative quantification without any chemical derivatization or manipulation.
This document discusses metabolic pathways and networks. It describes genome-scale metabolic models that include all known metabolic genes and reactions. These models can integrate omics data in a biologically meaningful way and be used to map genes, contextualize pathological states, and simulate drug effects. The document presents an application of metabolic network analysis to interpret urine metabolomics data from ADHD and autism patients to gain insights into disrupted tryptophan metabolism.
This document provides an overview of pharmacophore mapping and pharmacophore-based screening. It defines a pharmacophore as the pattern of molecular features responsible for a drug's biological activity. The key steps in pharmacophore modeling are identifying common binding elements in active compounds, generating potential ligand conformations, and determining the 3D relationships between pharmacophore elements. Pharmacophore models can be generated manually based on known active ligands or automatically using software. Receptor-based pharmacophore generation uses the 3D structure of the target protein to identify favorable binding sites. Overall, pharmacophore mapping is used in computer-aided drug design to identify novel ligands that interact with the same biological target.
Metabolic network mapping for metabolomicsDinesh Barupal
We present a novel approach to integrate biochemical pathway and chemical relationships to map all detected metabolites in network graphs (MetaMapp) using KEGG reactant pair database, Tanimoto chemical and NIST mass spectral similarity scores. In fetal and maternal lungs, and in maternal blood plasma from pregnant rats exposed to environmental tobacco smoke (ETS), 459 unique metabolites comprising 179 structurally identified compounds were detected by gas chromatography time of flight mass spectrometry (GC-TOF MS) and BinBase data processing. MetaMapp graphs in Cytoscape showed much clearer metabolic modularity and complete content visualization compared to conventional biochemical mapping approaches. Cytoscape visualization of differential statistics results using these graphs showed that overall, fetal lung metabolism was more impaired than lungs and blood metabolism in dams. Fetuses from ETS-exposed dams expressed lower lipid and nucleotide levels and higher amounts of energy metabolism intermediates than control animals, indicating lower biosynthetic rates of metabolites for cell division, structural proteins and lipids that are critical for in lung development.
MetaMapp graphs efficiently visualizes mass spectrometry based metabolomics datasets as network graphs in Cytoscape, and highlights metabolic alterations that can be associated with higher rate of pulmonary diseases and infections in children prenatally exposed to ETS. The MetaMapp scripts can be accessed at http://metamapp.fiehnlab.ucdavis.edu.
A New Platform for Combining the ‘Bottom-Up’ PBPK Paradigm and POPPK Data Ana...mjamei
The document discusses combining bottom-up physiologically-based pharmacokinetic (PBPK) modeling with top-down population pharmacokinetic (POPPK) data analysis. It describes current and previous Simcyp team members and grants received. It then contrasts top-down and bottom-up approaches, highlighting how the bottom-up approach can incorporate more physiological covariates compared to the empirical top-down approach. The document outlines Simcyp's parameter estimation module, which allows fitting simulations to clinical data to estimate population and drug parameters.
techniques used in Metabolite profiling of bryophytes pptUnnatiChopra1
The document discusses techniques used in metabolite profiling of bryophytes. It begins with an introduction to bryophytes and metabolite profiling. It then describes several techniques used for metabolite profiling including gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS), capillary electrophoresis-mass spectrometry (CE-MS), and nuclear magnetic resonance spectroscopy (NMR). Specific examples of how these techniques have been applied to study metabolite profiling in bryophytes are also provided. The document concludes with recommendations for future research and a summary of the importance of metabolite profiling.
Rushikesh Shinde presented on computational modeling of drug disposition at Alard College of Pharmacy. The presentation discussed how modeling absorption, solubility, and intestinal permeation can help predict drug behavior in the body. Historically, drug candidates often failed in late-stage clinical trials due to issues related to metabolism, excretion, and toxicity, which computational modeling seeks to evaluate earlier in the drug development process. The presentation covered techniques like quantitative structure-activity relationship analysis and pharmacokinetic modeling to computationally simulate drug properties.
Exploiting Edinburgh's Guide to PHARMACOLOGY database as a source of protein ...Chris Southan
Presented by Jamie Davies at the SULSA Synthetic Biology Meeting, Edinburgh, 10 June 2014
http://www.eventbrite.co.uk/e/sulsa-synthetic-biology-meeting-registration-11251454403?aff=eorg
Abstract: Synthetic creation of new biological systems typically incorporates pathways and signaling modules from known protein building blocks. Testing the models underpinning the synthetic engineering thus needs the experimental manipulation of individual proteins, for example, ablating a specific enzyme activity via RNAi, SNP mutation, or knockout. However, the option of small-molecule inhibition as the system perturbation has the advantages of 1) rapid onset 2) dose-response 3) analog testing for structure-activity relationships, 4) exploring mixtures for combinatorial effects 5) pulsing and reversal by wash-out. 6) accurate measurements of added substances and 7) a vast precedent of published results in natural systems from medicinal chemistry, pharmacology, and chemical biology. For the synthetic biologists the GToPdb1 can thus be considered as compendium of the latter. It encompasses an interaction matrix between ~4000 small molecules and ~1000 human proteins with a focus on drugs, clinical candidates, research compounds and peptide ligands These not only have ~ 10,000 mapped binding constants but also the spectrum of documented modulation extends across enzymes, receptors, channels and transporters. It thus becomes an increasingly plausible option to choose a “Lego protein” from GToPdb as a synthetic system component that can have experimentally useable activity probes available from chemical vendors. Even if it does not currently have a suitable target-probe pair, as knowledge base (and expertise resource via the curation team who populate it) GToPdb is an ideal starting point from which to walk out to wider chemogenomic spaces. For example, while an approved drug and its target might seem a logical choice, analogs from the lead series or different chemotypes from which the drug was optimized, or even failed in development, can have superior probe-like properties for in vitro experiments (e.g. be more potent, specific and soluble). The GToPdb facilitates access to such compound data via curated papers and patents.
References
1. Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SP, Buneman OP, Davenport AP, McGrath JC, Peters JA, Southan C, Spedding M, Yu W, Harmar AJ; NC-IUPHAR. The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands. Nucleic Acids Res. 2014 Jan 1;42(1)
This document discusses genomics and proteomics based drug discovery. It explains that genomics involves sequencing genomes to understand gene functions and interactions, while proteomics studies protein expression and interactions. The document outlines how structural bioinformatics and techniques like protein-ligand docking can help in drug target identification and rational drug design. It also discusses how proteomics can aid in various stages of drug discovery like target identification and validation.
INBIOMEDvision Workshop at MIE 2011. Victoria LópezINBIOMEDvision
1) Personalized medicine currently faces challenges in processing large-scale genomic data, interpreting the functional effects of genomic variations, integrating systems-level data, and translating discoveries into medical practice.
2) Bioinformatics can help address these challenges through algorithms for mapping and aligning sequencing data, predicting functional effects, prioritizing genes, integrating multi-omics data into networks, and disseminating discoveries through databases to inform medical practice.
3) Fully realizing personalized medicine will require overcoming limitations of current approaches, validating computational predictions, and updating medical practice and education to routinely incorporate genomic information.
Using computational models like pharmacophores and machine learning, researchers developed in silico models to predict interactions of drugs and compounds with important human drug transporters. Pharmacophore models of P-gp, ASBT, and OCTN2 were able to retrieve known substrates and inhibitors from databases and discover new interacting drug classes. A Bayesian model for ASBT performed well in classification, though external test sets remained challenging. Transporter models aid understanding of absorption, distribution, and toxicity of drugs.
Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both pre-approval and post-approval stages. There has been increased interest in developing predictive in vivo, in vitro and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study we applied machine learning, Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to internal validation. The Bayesian model with ECFC_6 fingerprint and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g. ketones, diols and -methyl styrene type structures. Using SMARTS filters published by several pharmaceutical companies we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, like the Abbott alerts which captures thiol traps and other compounds, may be of utility in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies for computational approaches. These computational models may represent a cost effective selection criteria prior to costly in vitro or in vivo experimental studies.
New regulations requiring toxicity data on chemicals and an increasing number of efforts to predict the likelihood of failure of molecules earlier in the drug discovery process are combining to increase the utilization of computational models to toxicity. The potential to predict human toxicity directly from a molecular structure is feasible. By using the experimental properties of known compounds as the basis of predictive models it is possible to develop structure activity relationships and resulting algorithms related to toxicity. Several examples have been published recently, including those for drug-induced liver injury (DILI), the pregnane X receptor, P450 3A4 time dependent inhibition, and transporters associated
with toxicities. The versatility and potential of using such models in drug discovery may be illustrated by increasing the efficiency of molecular screening and decreasing the number of animal studies. With more computational power available on increasingly smaller devices, as well as many collaborative initiatives to make data and toxicology models available, this may enable the development of mobile apps for predicting human toxicities, further increasing their utilization.
The document discusses computational models that have been and can be used for predicting human toxicities. It provides examples of models that have been developed for predicting various physicochemical properties, interactions with proteins, and toxicity outcomes like mutagenicity, environmental toxicity, and drug-induced liver injury. It also outlines future areas that could be modeled, like mixtures and more specific protein targets. The key enablers of these models are increased computing power and data availability from literature and open sources.
This document describes a study that used co-immunoprecipitation and mass spectrometry to identify protein interaction partners of protein phosphatase 2A (PP2A) catalytic subunit in human skeletal muscle. 135 potential interaction partners were identified from muscle biopsies of 17 subjects. Many of the partners are involved in important signaling pathways related to insulin signaling and resistance. The interaction network provides insight into how PP2A regulates these pathways. Comparing partners between lean, obese, and diabetic groups may help understand differences in PP2A regulation related to insulin resistance.
This document provides an overview of the International Union of Basic and Clinical Pharmacology Guide to Pharmacology (GtoPdb) database. It describes the database contents including over 1,700 drug targets and 9,400 ligands. The database is curated by 500 experts and provides target and ligand information for researchers. Specialized versions of the database have also been created for immunopharmacology and malaria research.
Bioanalytical Method Development and Validation for the Estimation of Metopro...BRNSSPublicationHubI
This document describes the development and validation of a bioanalytical method for quantifying metoprolol, a beta-blocker, in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method involves extracting metoprolol from human K2EDTA plasma followed by LC-MS/MS analysis. The method was validated based on parameters including selectivity, sensitivity, linearity, accuracy, precision, recovery, matrix effect, dilution integrity and stability. The validated method was successfully applied to quantify metoprolol concentrations in human plasma samples for pharmacokinetic studies.
Genomics and proteomics in drug discovery and developmentSuchittaU
This document discusses the role of genomics and proteomics in drug discovery and development. It explains that genomics and proteomics technologies can help identify new drug targets by comparing gene and protein expression between healthy and diseased cells. Proteomics in particular analyzes changes in protein levels and can quantify individual proteins using techniques like 2D gel electrophoresis and mass spectrometry. The integration of genomics and proteomics provides a more comprehensive understanding of biological systems and is improving the drug discovery process.
Potential role of bioactive peptides in prevention and treatment of chronic d...NxFxProducerDJ
This review analyzes studies and clinical trials on bioactive peptides and their potential roles in preventing and treating chronic diseases. The review focuses on cardiovascular diseases, immunity, cancer, and other areas. Bioactive peptides from various food sources like fish, milk, meat, and plants have shown effects like lowering blood pressure and lipids in clinical trials. Some peptides also demonstrate anticancer activity in vitro and in vivo as well as immunomodulatory and antimicrobial effects. However, more clinical evidence and standardized extraction procedures are still needed to confirm these effects and enable use of bioactive peptides as preventive or therapeutic treatments.
Talk at Yale University April 26th 2011: Applying Computational Modelsfor To...Sean Ekins
The document discusses applying computational models to problems in toxicology, drug discovery, and beyond. It summarizes recent work using machine learning models and other in silico techniques to predict drug-induced liver injury (DILI) and interactions with transporters like hOCTN2. Models were able to classify compounds as DILI-positive or negative with over 75% accuracy when tested on external datasets. The techniques discussed could help prioritize compounds for further testing and filter libraries to avoid reactive or toxic features.
The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb) is an expert-driven, open database of pharmacological targets and the substances that act on them. It contains information on over 1,800 drug targets and 1,100 related proteins. The database is curated by 500 experts and provides detailed pharmacological data as well as overviews of key properties and ligands. Specialized extensions of GtoPdb include guides to immunopharmacology and malaria pharmacology that connect their fields to drug discovery. The database is continuously updated with new targets, ligands, features and access methods.
Computational modelling of drug disposition lalitajoshi9
computational modelling of drug disposition is the integral part of computer aided drug design. different kinds of tools being used in the prediction of drug disposition in human body. This topic in the CADD explains the details about the drug disposition, active transporters and tools.
The IUPHAR/BPS Guide to PHARAMCOLOGY in 2018: new features and updatesGuide to PHARMACOLOGY
2018 update poster for the IUPHAR/BPS Guide to PHARMACOLOGY. Giving details of new features and updates. To be presented at Pharmacology Futures, Edinburgh, May 2018; ELIXIR-All Hands, Berlin, June 2018 and World Congress of Pharmacology, Kyoto, Japan, July 2018
This document derives Biomonitoring Equivalents (BEs) for triclosan based on recent health risk assessments and pharmacokinetic data. BEs provide screening values to evaluate biomonitoring data in a health risk context. The US EPA, EC, and Australian risk assessments identified no-observed-adverse-effect levels and reference doses for triclosan. Based on human and animal pharmacokinetic studies, the document estimates BE values in urine and plasma corresponding to the exposure guidelines. The urinary BEs were 6.4 and 2.6 mg/L, and the plasma BEs were 0.3, 0.9, and 0.4 mg/L corresponding to the different risk
Bioanalysis is the quantitative measurement of drugs, metabolites, and biological molecules in biological systems. It plays an important role in drug discovery and development by supporting pharmacokinetic studies. The drug development process involves preclinical and clinical stages where bioanalysis is used to determine safety, identify metabolites, and understand pharmacokinetics. Techniques like liquid chromatography-mass spectrometry are commonly used for bioanalysis of small molecules and large molecules during drug development.
The document summarizes recent updates to the IUPHAR/BPS Guide to PHARMACOLOGY database. It describes new features including expanded target coverage with over 1,700 drug targets and 1,100 related proteins. A new Pharmacology Search Tool allows users to upload protein lists and find associated ligands. The database also now connects immunopharmacology by associating targets with immune processes, cell types, and diseases. Additionally, the guide describes collaborations to include antimalarial compound data and develop an IUPHAR/MMV Guide to Malaria Pharmacology.
Similar to Poster on systems pharmacology of the cholesterol biosynthesis pathway (20)
Presentation by Dr. Elena Faccenda on the IUPHAR/BPS Guide to Immunopharmacology at the 39° Congresso Nazionale della Società Italiana di Farmacologia in Florence, Nov 2019
This document discusses the IUPHAR/BPS Guide to Pharmacology database and related resources. It provides open access information on pharmacological targets and the substances that act on them. It includes over 1,700 human drug targets, 9,700 ligands including 1,300 approved drugs. Related databases include the Guide to Immunopharmacology and Guide to Malaria Pharmacology. The databases are regularly updated and include links to other resources to enable interoperability.
1) Researchers have created a new online resource called the IUPHAR/MMV Guide to Malaria Pharmacology (GtoMPdb) to curate information on antimalarial compounds and their molecular targets in Plasmodium.
2) The database currently contains 25 Plasmodium molecular targets and 57 antimalarial ligands that were manually curated from scientific literature.
3) A new customized online portal provides open access to the antimalarial data and allows browsing by parasite lifecycle stage, target species, and other features to help malaria research.
The document provides an overview and progress report on database activities from April 2018 - March 2019. Key points include:
- Publications in peer-reviewed journals on the database and new immunopharmacology guide.
- Engagement through conferences, social media, and interactions with users seeking to improve the database.
- Ongoing development of the database interface and content, including expansion to new therapeutic areas.
- Statistics on usage, file downloads, and web service calls that show increasing interaction over time.
Dr. Simon D. Harding of the University of Edinburgh created a knowledge-base that connects immunology and pharmacology. The knowledge-base links immunological targets and ligands to cell types and diseases. It is part of the IUPHAR/BPS Guide to Pharmacology, an open database of drug targets and ligands including approved drugs. A new search tool allows searching of pharmacological information. Dr. Harding also aims to curate data on antimalarial compounds and their molecular targets in Plasmodium through the IUPHAR/MMV Guide to Malaria Pharmacology.
Poster on GtoImmuPdb presented at European Congress of Immunology (Amsterdam, Sep 2018). Overview of the main data types and features included in this extension to the IUPHAR/BPS Guide to PHARMACOLOGY
The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb) is an open, expert-driven database that contains information on over 1,700 pharmacological targets and the substances that act on them. The database provides overviews and detailed information on targets that is manually curated from literature and reviewed by experts. It aims to cover human drug targets and potential future therapeutic targets. New features of the database include search tools to find targets and ligands, information on diseases associated with targets and ligands, organization of ligand families, and comparison of ligand activity across species. The database content is available to download in various formats and its interoperability has been increased through developing an RDF version and submitting data to other sources
The document provides an overview and status report of the Core Guide to PHARMACOLOGY (GtoPdb) database. It discusses recent publications from the team, compliance with new GDPR privacy regulations, website access statistics showing increased usage, new website features, and priorities for further development such as expanding disease and content coverage.
The document provides a status report on the Guide to Immunopharmacology database (GtoImmuPdb). It discusses developments including the addition of disease data, graphical browsing of cell type data, and process data. The database is in beta version 3 and undergoing user testing. Over 500 targets and 1,000 ligands have been curated from the literature. On the curation side, efforts are focused on expanding the literature collection and annotating new targets and ligands. The database is preparing for its official launch in October 2018.
Updated poster following beta v3 release. In preparation for Pharmacology Futures, Edinburgh Immunology Symposium and Word Congress of Pharmacology (Kyoto)
IUPHAR/BPS Guide to PHARMACOLOGY in 2017: new features and updatesGuide to PHARMACOLOGY
This document summarizes updates to the IUPHAR/BPS Guide to PHARMACOLOGY database. It provides expert curated data on human drug targets and ligands. Recent additions include new target families, ligands, and links to immunopharmacology data. New features include download options, search tools, and organization of ligand families. The database is maintained by an international team and network of scientists and provides a resource for pharmacology education and research.
These slides will be presented at the Pharmacology 2017 meeting in London during the following session:
Abstract Number: OB073
Abstract Title: Capturing new BIA 10-2474 molecular data in the IUPHAR/BPS Guide to PHARMACOLOGY
Date: Wednesday, December 13, 2017, 11:30 AM
Oral Session: Oral Communications: Mixed Tracks
This comprehensive slide deck is provided for use by those who are teaching and presenting on the IUPHAR/BPS Guide to PHARMACOLOGY. Includes:
- Overview of NC-IUPHAR
- Background to GtoPdb
- Screenshots of the website and search tools
- Recent content expansions
- Other features and initiatives including the Guide to IMMUNOPHARMACOLOGY
This slide set updates the previous set from 2014/15 available at https://www.slideshare.net/GuidetoPHARM/iupharbps-guide-to-pharmacology-generic-slideset
Navigating links between structures and papers:
PubMed-to-PubChem connectivity between the IUPHAR/BPS Guide to PHARMACOLOGY and British Journal of Pharmacology
A poster presented at Pharmacology 2017, London, December 2017
A general poster about the IUPHAR/BPS Guide to PHARMACOLOGY, updated for 2017. This works well used as a handout or pinned on departmental noticeboards.
IUPHAR Guide to IMMUNOPHARMACOLOGY poster. Presented at the BSI Congress 2017, Brighton, UK (6th December 2017) and at Pharmacology 2017, London, UK (13th December 2017.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
ESR spectroscopy in liquid food and beverages.pptxPRIYANKA PATEL
With increasing population, people need to rely on packaged food stuffs. Packaging of food materials requires the preservation of food. There are various methods for the treatment of food to preserve them and irradiation treatment of food is one of them. It is the most common and the most harmless method for the food preservation as it does not alter the necessary micronutrients of food materials. Although irradiated food doesn’t cause any harm to the human health but still the quality assessment of food is required to provide consumers with necessary information about the food. ESR spectroscopy is the most sophisticated way to investigate the quality of the food and the free radicals induced during the processing of the food. ESR spin trapping technique is useful for the detection of highly unstable radicals in the food. The antioxidant capability of liquid food and beverages in mainly performed by spin trapping technique.
Or: Beyond linear.
Abstract: Equivariant neural networks are neural networks that incorporate symmetries. The nonlinear activation functions in these networks result in interesting nonlinear equivariant maps between simple representations, and motivate the key player of this talk: piecewise linear representation theory.
Disclaimer: No one is perfect, so please mind that there might be mistakes and typos.
dtubbenhauer@gmail.com
Corrected slides: dtubbenhauer.com/talks.html
ESPP presentation to EU Waste Water Network, 4th June 2024 “EU policies driving nutrient removal and recycling
and the revised UWWTD (Urban Waste Water Treatment Directive)”
The binding of cosmological structures by massless topological defectsSérgio Sacani
Assuming spherical symmetry and weak field, it is shown that if one solves the Poisson equation or the Einstein field
equations sourced by a topological defect, i.e. a singularity of a very specific form, the result is a localized gravitational
field capable of driving flat rotation (i.e. Keplerian circular orbits at a constant speed for all radii) of test masses on a thin
spherical shell without any underlying mass. Moreover, a large-scale structure which exploits this solution by assembling
concentrically a number of such topological defects can establish a flat stellar or galactic rotation curve, and can also deflect
light in the same manner as an equipotential (isothermal) sphere. Thus, the need for dark matter or modified gravity theory is
mitigated, at least in part.
What is greenhouse gasses and how many gasses are there to affect the Earth.moosaasad1975
What are greenhouse gasses how they affect the earth and its environment what is the future of the environment and earth how the weather and the climate effects.
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/
EWOCS-I: The catalog of X-ray sources in Westerlund 1 from the Extended Weste...Sérgio Sacani
Context. With a mass exceeding several 104 M⊙ and a rich and dense population of massive stars, supermassive young star clusters
represent the most massive star-forming environment that is dominated by the feedback from massive stars and gravitational interactions
among stars.
Aims. In this paper we present the Extended Westerlund 1 and 2 Open Clusters Survey (EWOCS) project, which aims to investigate
the influence of the starburst environment on the formation of stars and planets, and on the evolution of both low and high mass stars.
The primary targets of this project are Westerlund 1 and 2, the closest supermassive star clusters to the Sun.
Methods. The project is based primarily on recent observations conducted with the Chandra and JWST observatories. Specifically,
the Chandra survey of Westerlund 1 consists of 36 new ACIS-I observations, nearly co-pointed, for a total exposure time of 1 Msec.
Additionally, we included 8 archival Chandra/ACIS-S observations. This paper presents the resulting catalog of X-ray sources within
and around Westerlund 1. Sources were detected by combining various existing methods, and photon extraction and source validation
were carried out using the ACIS-Extract software.
Results. The EWOCS X-ray catalog comprises 5963 validated sources out of the 9420 initially provided to ACIS-Extract, reaching a
photon flux threshold of approximately 2 × 10−8 photons cm−2
s
−1
. The X-ray sources exhibit a highly concentrated spatial distribution,
with 1075 sources located within the central 1 arcmin. We have successfully detected X-ray emissions from 126 out of the 166 known
massive stars of the cluster, and we have collected over 71 000 photons from the magnetar CXO J164710.20-455217.
ANAMOLOUS SECONDARY GROWTH IN DICOT ROOTS.pptxRASHMI M G
Abnormal or anomalous secondary growth in plants. It defines secondary growth as an increase in plant girth due to vascular cambium or cork cambium. Anomalous secondary growth does not follow the normal pattern of a single vascular cambium producing xylem internally and phloem externally.
Nucleophilic Addition of carbonyl compounds.pptxSSR02
Nucleophilic addition is the most important reaction of carbonyls. Not just aldehydes and ketones, but also carboxylic acid derivatives in general.
Carbonyls undergo addition reactions with a large range of nucleophiles.
Comparing the relative basicity of the nucleophile and the product is extremely helpful in determining how reversible the addition reaction is. Reactions with Grignards and hydrides are irreversible. Reactions with weak bases like halides and carboxylates generally don’t happen.
Electronic effects (inductive effects, electron donation) have a large impact on reactivity.
Large groups adjacent to the carbonyl will slow the rate of reaction.
Neutral nucleophiles can also add to carbonyls, although their additions are generally slower and more reversible. Acid catalysis is sometimes employed to increase the rate of addition.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
The use of Nauplii and metanauplii artemia in aquaculture (brine shrimp).pptxMAGOTI ERNEST
Although Artemia has been known to man for centuries, its use as a food for the culture of larval organisms apparently began only in the 1930s, when several investigators found that it made an excellent food for newly hatched fish larvae (Litvinenko et al., 2023). As aquaculture developed in the 1960s and ‘70s, the use of Artemia also became more widespread, due both to its convenience and to its nutritional value for larval organisms (Arenas-Pardo et al., 2024). The fact that Artemia dormant cysts can be stored for long periods in cans, and then used as an off-the-shelf food requiring only 24 h of incubation makes them the most convenient, least labor-intensive, live food available for aquaculture (Sorgeloos & Roubach, 2021). The nutritional value of Artemia, especially for marine organisms, is not constant, but varies both geographically and temporally. During the last decade, however, both the causes of Artemia nutritional variability and methods to improve poorquality Artemia have been identified (Loufi et al., 2024).
Brine shrimp (Artemia spp.) are used in marine aquaculture worldwide. Annually, more than 2,000 metric tons of dry cysts are used for cultivation of fish, crustacean, and shellfish larva. Brine shrimp are important to aquaculture because newly hatched brine shrimp nauplii (larvae) provide a food source for many fish fry (Mozanzadeh et al., 2021). Culture and harvesting of brine shrimp eggs represents another aspect of the aquaculture industry. Nauplii and metanauplii of Artemia, commonly known as brine shrimp, play a crucial role in aquaculture due to their nutritional value and suitability as live feed for many aquatic species, particularly in larval stages (Sorgeloos & Roubach, 2021).
Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...AbdullaAlAsif1
The pygmy halfbeak Dermogenys colletei, is known for its viviparous nature, this presents an intriguing case of relatively low fecundity, raising questions about potential compensatory reproductive strategies employed by this species. Our study delves into the examination of fecundity and the Gonadosomatic Index (GSI) in the Pygmy Halfbeak, D. colletei (Meisner, 2001), an intriguing viviparous fish indigenous to Sarawak, Borneo. We hypothesize that the Pygmy halfbeak, D. colletei, may exhibit unique reproductive adaptations to offset its low fecundity, thus enhancing its survival and fitness. To address this, we conducted a comprehensive study utilizing 28 mature female specimens of D. colletei, carefully measuring fecundity and GSI to shed light on the reproductive adaptations of this species. Our findings reveal that D. colletei indeed exhibits low fecundity, with a mean of 16.76 ± 2.01, and a mean GSI of 12.83 ± 1.27, providing crucial insights into the reproductive mechanisms at play in this species. These results underscore the existence of unique reproductive strategies in D. colletei, enabling its adaptation and persistence in Borneo's diverse aquatic ecosystems, and call for further ecological research to elucidate these mechanisms. This study lends to a better understanding of viviparous fish in Borneo and contributes to the broader field of aquatic ecology, enhancing our knowledge of species adaptations to unique ecological challenges.
BREEDING METHODS FOR DISEASE RESISTANCE.pptxRASHMI M G
Plant breeding for disease resistance is a strategy to reduce crop losses caused by disease. Plants have an innate immune system that allows them to recognize pathogens and provide resistance. However, breeding for long-lasting resistance often involves combining multiple resistance genes
Poster on systems pharmacology of the cholesterol biosynthesis pathway
1. 3. Results (I)
2. Pathway production
6. References
1 Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh, UK. 2 Northern Ireland Centre for Stratified Medicine, University of Ulster, C-Tric, Derry,
UK (current addresses for HEB and CPM are given in reference [2])
www.guidetopharmacology.org enquiries@guidetopharmacology.org @GuidetoPHARM
A systems pharmacology study of the cholesterol
biosynthesis pathway
Supported by:
We especially thank all contributors, collaborators and NC-IUPHAR members
1. Introduction
Information on drugs, lead compounds and their pharmacological effects is expanding
in online resources, including the IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb)
[1]. This means that for key pathways and modules there is an expansion in the number
of data-supported druggable targets captured in databases. As this catalogue of
molecular interactions and our understanding of biological systems expands, it will be
advantageous to integrate these resources in order to devise new potential therapies.
Drug combinations present an opportunity for therapy development that can target
pathways more precisely than perturbing entire networks. Systems pharmacology will
also impact genomic medicine, including personalisation of treatments and stratification
of patient groups. Thus, as our understanding increases, we have opportunities to
predict, model, quantify and test combinations that may have advantages over
conventional single-drug therapies. This work explores the feasibility of such systems
pharmacology approaches with an analysis of the mevalonate branch of the cholesterol
biosynthesis pathway. This poster is a summary of a detailed paper published in Sept
2017 that also includes extensive supplementary data [2].
Updates of our extensive curation of the pathway are now in GtoPdb as below.
Figure 1. These snap shots are taken from the pathway display in:
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=104
The summary links specify the protein properties and detailed pages display kinetic
parameters along with substrates and inhibitors for the enzymes as ligand entries.
Figure 1. Examples of various kinase database tables
1. Harding SD, et al. (2018) The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: Updates and expansion to encompass
the new Guide to IMMUNOPHARMACOLOGY. Nucl. Acids Res. 46 (Database Issue). doi: 10.1093/nar/gkx1121.
2. Benson, HE et al, (2017) Is systems pharmacology ready to impact upon therapy development? A study on the
cholesterol biosynthesis pathway. Br. J. Pharmacol. Sep 14. doi: 10.1111/bph.14037. [Epub ahead of print]
3. Mazein A et al. (2013) A comprehensive machine-readable view of the mammalian cholesterol biosynthesis pathway.
Biochem Pharmacol. 86(1):56-66. doi: 10.1016/j.bcp.2013.03.021
.
GtoPdb is an ELIXIR UK node resource
4. Model of the mevalonate arm of the cholesterol pathway
We produced a model of the mevalonate arm of the cholesterol biosynthesis pathway in
Systems Biology Graphical Notation (SBGN) for the metabolic steps from acetyl-CoA
and acetoacetyl-CoA consumption to squalene and geranylgeranyl diphosphate
production. This comprises 12 steps, 10 enzymes and 14 metabolites.
Figure 2. The full enzyme names for this pathway diagram are in Fig.1
We used the model to calculate steady-state flux profiles without inhibitors and then
tested the affects of drug combinations on fluxes via computational optimization. We
determined a combination of five inhibitors showed the desired suppression squalene
while maintaining normal geranyl diphosphate levels (full details are available in [2])
Christopher Southan1, Helen E. Benson1, Steven Watterson2, Joanna L. Sharman1,
Chido P. Mpamhanga1 and Andrew Parton2
5. Conclusions
Our initial attempts to build a systems pharmacology model of the mevalonate arm of
the cholesterol biosynthesis pathway revealed gaps and inconsistencies in the data that
prevented us from achieving a high level of confidence. In particular, we found the lack
of comprehensive and systematic parameterizations, experimental variation, ambiguity
in structural detail and inappropriate and inaccurate reporting from the primary literature
to be obstacles. That this should be the case for a pathway of such high biomedical and
commercial significance was unexpected. For this reason, our best current
parameterization represents a patchwork of values taken from multiple species and
experimental configurations. Nonetheless, by completing gaps in our knowledge with
representative values, we were able to demonstrate subtle reprogramming of pathway
dynamics that may contribute significantly to drug development. We propose that these
obstacles can be reduced through the adoption of standards and quality control.
Although we have focused on the mevalonate arm of cholesterol biosynthesis, this
approach could be applied to any pathway of interest for which targets, ligands and
kinetic parameters are known. Note also that GtoPdb expands the capture of ligand-to-
target relationships every release. However, extending modelling opportunities more
generally needs both the computational biology and the pharmacology communities to
reduce barriers to progress. The model from this work and our previous study [3] is
available from http://biomodels.org (ID 1506220000) and can freely be used and
adapted.
We combined the interrogation of multiple databases and cross-checking primary
literature to establish the enzymes involved in the pathway, the reactions they
catalyse, subcellular localization, species in which they were identified, substrate,
kinetic parameters and inhibitors. This uncovered some inconsistences and
ambiguities in database entries that we had to resolve against data specified in the
papers. We combined ordinary differential equation (ODE) kinetic models, the
pathway parameters and the inhibitor parameters to create a model describing the
dynamics of the mevalonate pathway. This incorporated Michaelis–Menten kinetics
to describe each step, except the interactions consuming isopentenyl diphosphate
and producing geranylgeranyl diphosphate and pre-squalene diphosphate. These
steps were described using mass action kinetics in order to simplify the process of
calculating the steady state of the model and hence the steady state behaviour of
the pathway. We then sought to identify the drug combination that would best
suppress the production of squalene as a precursor for cholesterol, but would also
maintain production of geranylgeranyl-diphosphate at the same levels as in the
absence of any inhibitors, thereby eliminating a significant side-effect of treatment.
After establishing the steady-state activity of the pathway in the absence of
inhibitors, we then we used computational optimization to identify a drug
combination that, at steady state, minimized squalene production, but left
geranylgeranyl diphosphate production the same as in the absence of inhibitors.