Selected project impacts from over a decade of using insights from computational chemistry Focus on heterocyclic rings in candidate drugs discovered at AstraZeneca/CVMD and the strategies used in their design. The case stories will include a wide variety of examples, such as (i) replacing unwanted functional groups like acids and esters with heterocyclic rings, (ii) using rings for geometrical reasons and (iii) using heterocyclic rings to fine-tune electrostatics to obtain improved properties. In most cases the key computational approach for designing candidate drugs has been the use of shape and electrostatic comparisons between molecules. The role of luck is also discussed.
The halo(gen) effect in para substituted phenyl rings - EuroCup2015Jonas Boström
One key to successfully progress a drug discovery project is to make first-rate decisions (hopefully) based on unambiguous data. This is not trivial since our scientific problems are often very complex and data can be fuzzy. In drug design we try to approach this uncertainty by being rational. It is however sometimes forgotten that our rational approaches may not be that rational after all – decisions may well be based on personal preferences and intuitive biases.... perhaps unconsciously made on biased data
Structural Isosteres of Phosphate Groups in the Protein Data Bank - ACS DC 2017Alexandre Borrel
In this work, we developed a computational workflow to mine the Protein Data Bank for isosteric replacements that exist in different binding site environments but have not necessarily been identified and exploited in compound design. Taking phosphate groups as examples, the workflow was used to construct 157 data sets, each composed of a reference protein complexed with AMP, ADP, ATP, or pyrophosphate as well other ligands. Phosphate binding sites appear to have a high hydration content and large size, resulting in U-shaped bioactive conformations recurrently found across unrelated protein families. A total of 16 413 replacements were extracted, filtered for a significant structural overlap on phosphate groups, and sorted according to their SMILES codes, see workflow in Figure 1. In addition to classical isosteres of phosphate, we found unexpected types of replacements that do not conserve charge or polarity, for example phosphate replaced by aliphatic groups, phenyl, or carbamoyl groups. The structural mechanism involved in structural isosteres appears varied: New interactions may be created, water molecules are important, in some case ion plays a role, and of course large and small conformational changes do occur at the binding sites. This study has implications both in the field of medicinal chemistry, i.e. it expands our knowledge of structural isosteres, and in the field of chemoinformatics, since our results have implications with respect to the definitions of chemical similarity.
The halo(gen) effect in para substituted phenyl rings - EuroCup2015Jonas Boström
One key to successfully progress a drug discovery project is to make first-rate decisions (hopefully) based on unambiguous data. This is not trivial since our scientific problems are often very complex and data can be fuzzy. In drug design we try to approach this uncertainty by being rational. It is however sometimes forgotten that our rational approaches may not be that rational after all – decisions may well be based on personal preferences and intuitive biases.... perhaps unconsciously made on biased data
Structural Isosteres of Phosphate Groups in the Protein Data Bank - ACS DC 2017Alexandre Borrel
In this work, we developed a computational workflow to mine the Protein Data Bank for isosteric replacements that exist in different binding site environments but have not necessarily been identified and exploited in compound design. Taking phosphate groups as examples, the workflow was used to construct 157 data sets, each composed of a reference protein complexed with AMP, ADP, ATP, or pyrophosphate as well other ligands. Phosphate binding sites appear to have a high hydration content and large size, resulting in U-shaped bioactive conformations recurrently found across unrelated protein families. A total of 16 413 replacements were extracted, filtered for a significant structural overlap on phosphate groups, and sorted according to their SMILES codes, see workflow in Figure 1. In addition to classical isosteres of phosphate, we found unexpected types of replacements that do not conserve charge or polarity, for example phosphate replaced by aliphatic groups, phenyl, or carbamoyl groups. The structural mechanism involved in structural isosteres appears varied: New interactions may be created, water molecules are important, in some case ion plays a role, and of course large and small conformational changes do occur at the binding sites. This study has implications both in the field of medicinal chemistry, i.e. it expands our knowledge of structural isosteres, and in the field of chemoinformatics, since our results have implications with respect to the definitions of chemical similarity.
Ontomine, a US Patent pending software algorithm is used to search for novel non-nucleoside reverse transcriptase inhibitors of HIV.
An sdf database of about 900,000 small molecules from pubchem is screened using information derived from 4 well known inhibitors.
It is shown that the results are novel, highly accurate with reference to known biological activity from assays and that the method is better than docking.
Ontomine based scaffold hopping identifies diverse molecules starting with a few known drugs and can be used instead of OR alongside docking methodologies.
As a requirement of the MYP programme (an international scholastic programme adopted by international schools around the world), it's needed to fulfill a "personal project". A personal project is an individual project and should focus on a topic of interest for the student.
I've decided to do my personal project on raising awareness to teenagers about cannabis. As I myself am a teenager in the Netherlands, the presentation includes statistics mainly for Holland, only.
Of course, elaborations of the bullet points on the slides would've been made had this presentation been oral, as well.
Thanks for watching and please comment and give feedback!
Pier
Fragment screening library workshop (IQPC 2008)Peter Kenny
I also ran a workshop on selection of compounds for fragment screening just before the 2008 IQPC compound library conference and these are the slides I used.
Harder-to-treat and more lethal tubercle bacilli continue to emerge across the globe, especially in the African region. Together with HIV, these infectious killers continue to have profound effects on the productive workforce in different countries. The deck is a brief overview of developments in disease management and research, with an emphasis on medications and vaccines.
A seminar presentation I made as part of my residency. The drugs covered are Synthetic Cathinones, Synthetic Cannabinoids, Ecstacy/MDMA, GHB, Ketamine and Mephedrone.
The video for this presentation is available on our Youtube channel:
https://youtube.com/allceuseducation A continuing education course for this presentation can be found at https://www.allceus.com/member/cart/index/index?c=
Objectives
Identify the symptoms of marijuana intoxication
Review the research related to the short and long term effects of marijuana on the brain and body
Explore the medical uses of marijuana
Discuss marijuana as a gateway drug
What is It
Marijuana refers to the dried leaves, flowers, stems, and seeds from the hemp plant, Cannabis sativa.
The plant contains the mind-altering chemical delta-9-tetrahydrocannabinol (THC)
Extracts with high amounts of THC can also be made from the cannabis plant
How is it Used
Smoked
Joints
Pipes or water pipes (bongs)
Blunts—emptied cigars that have been partly or completely refilled with marijuana.
Vaporized
Pull the active ingredients from the marijuana and collect their vapor in a storage unit which is inhaled instead of smoke.
Eaten: Brownies, cookies, or candy, or brew it as a tea.
How is it Used
Resins: A newly popular method of use is smoking or eating different forms of THC-rich resins
Smoking THC-rich resins extracted from the marijuana plant is on the rise. Users call this practice dabbing. People are using various forms of these extracts, such as:
hash oil or honey oil—a gooey liquid
wax or budder—a soft solid with a texture like lip balm
shatter—a hard, amber-colored solid
Oral Ingestion
Orally consumed cannabinoids tends to be stronger and last longer (4-6 hours) than inhaled cannabis.
This is because of the way bodies metabolize THC.
When cannabis is inhaled, THC passes rapidly from the lungs to the blood stream and to the brain.
When cannabis is consumed orally, a significant portion of THC is converted into the metabolite 11-hydroxy-THC before reaching the brain.
This metabolite is believed to be slightly more potent than THC and possesses a greater blood-brain penetrability
Short Term Effects
THC effects are felt more slowly when the person eats or drinks it. (30 minutes to 1 hour)
Effects
Altered senses (for example, seeing brighter colors)
Temporary hallucinations
Altered sense of time
Changes in mood
Impaired body movement
Difficulty with thinking and problem-solving
Impaired memory
Breathing problems. Marijuana smoke irritates the lungs
Increased heart rate for up to 3 hours after smoking
Synthetic Cannabinoids such as kratom are psychoactive designer drugs derived of natural herbs sprayed with synthetic chemicals that, when consumed, allegedly mimic the pleasurable effects of cannabinoids.
Obesity is one of the most common factor which underlies the pathophysiology of many other non- communicable diseases. In recent years, its prevalence has blown out of proportions. The term GLOBESITY signfies that. Newer pharmacological developments will definitely play a crucial role in containing this epidemic.
This seminar is my attempt this interesting topic with all the latest data I could collect on the internet.
Ontomine, a US Patent pending software algorithm is used to search for novel non-nucleoside reverse transcriptase inhibitors of HIV.
An sdf database of about 900,000 small molecules from pubchem is screened using information derived from 4 well known inhibitors.
It is shown that the results are novel, highly accurate with reference to known biological activity from assays and that the method is better than docking.
Ontomine based scaffold hopping identifies diverse molecules starting with a few known drugs and can be used instead of OR alongside docking methodologies.
As a requirement of the MYP programme (an international scholastic programme adopted by international schools around the world), it's needed to fulfill a "personal project". A personal project is an individual project and should focus on a topic of interest for the student.
I've decided to do my personal project on raising awareness to teenagers about cannabis. As I myself am a teenager in the Netherlands, the presentation includes statistics mainly for Holland, only.
Of course, elaborations of the bullet points on the slides would've been made had this presentation been oral, as well.
Thanks for watching and please comment and give feedback!
Pier
Fragment screening library workshop (IQPC 2008)Peter Kenny
I also ran a workshop on selection of compounds for fragment screening just before the 2008 IQPC compound library conference and these are the slides I used.
Harder-to-treat and more lethal tubercle bacilli continue to emerge across the globe, especially in the African region. Together with HIV, these infectious killers continue to have profound effects on the productive workforce in different countries. The deck is a brief overview of developments in disease management and research, with an emphasis on medications and vaccines.
A seminar presentation I made as part of my residency. The drugs covered are Synthetic Cathinones, Synthetic Cannabinoids, Ecstacy/MDMA, GHB, Ketamine and Mephedrone.
The video for this presentation is available on our Youtube channel:
https://youtube.com/allceuseducation A continuing education course for this presentation can be found at https://www.allceus.com/member/cart/index/index?c=
Objectives
Identify the symptoms of marijuana intoxication
Review the research related to the short and long term effects of marijuana on the brain and body
Explore the medical uses of marijuana
Discuss marijuana as a gateway drug
What is It
Marijuana refers to the dried leaves, flowers, stems, and seeds from the hemp plant, Cannabis sativa.
The plant contains the mind-altering chemical delta-9-tetrahydrocannabinol (THC)
Extracts with high amounts of THC can also be made from the cannabis plant
How is it Used
Smoked
Joints
Pipes or water pipes (bongs)
Blunts—emptied cigars that have been partly or completely refilled with marijuana.
Vaporized
Pull the active ingredients from the marijuana and collect their vapor in a storage unit which is inhaled instead of smoke.
Eaten: Brownies, cookies, or candy, or brew it as a tea.
How is it Used
Resins: A newly popular method of use is smoking or eating different forms of THC-rich resins
Smoking THC-rich resins extracted from the marijuana plant is on the rise. Users call this practice dabbing. People are using various forms of these extracts, such as:
hash oil or honey oil—a gooey liquid
wax or budder—a soft solid with a texture like lip balm
shatter—a hard, amber-colored solid
Oral Ingestion
Orally consumed cannabinoids tends to be stronger and last longer (4-6 hours) than inhaled cannabis.
This is because of the way bodies metabolize THC.
When cannabis is inhaled, THC passes rapidly from the lungs to the blood stream and to the brain.
When cannabis is consumed orally, a significant portion of THC is converted into the metabolite 11-hydroxy-THC before reaching the brain.
This metabolite is believed to be slightly more potent than THC and possesses a greater blood-brain penetrability
Short Term Effects
THC effects are felt more slowly when the person eats or drinks it. (30 minutes to 1 hour)
Effects
Altered senses (for example, seeing brighter colors)
Temporary hallucinations
Altered sense of time
Changes in mood
Impaired body movement
Difficulty with thinking and problem-solving
Impaired memory
Breathing problems. Marijuana smoke irritates the lungs
Increased heart rate for up to 3 hours after smoking
Synthetic Cannabinoids such as kratom are psychoactive designer drugs derived of natural herbs sprayed with synthetic chemicals that, when consumed, allegedly mimic the pleasurable effects of cannabinoids.
Obesity is one of the most common factor which underlies the pathophysiology of many other non- communicable diseases. In recent years, its prevalence has blown out of proportions. The term GLOBESITY signfies that. Newer pharmacological developments will definitely play a crucial role in containing this epidemic.
This seminar is my attempt this interesting topic with all the latest data I could collect on the internet.
UCSD Deans and Chairs Presentation - PDB & Drug DiscoveryPhilip Bourne
A presentation made to the Deans and Chairs of the UCSD Health Sciences on Jan. 25, 2011 concerning the role that the PDB might play in drug discovery going forward.
Presentation on March 12, 2011 at the Skaggs School of Pharmacy and Pharmaceutical Sciences (UCSD) during the Workshop in Allosteric and Orthosteric Ligands in Drug Action
this will be useful to understand about the new topics such as abzymes, ribozymes and also isoenzymes. You have to clear that ribozymes are not protein. because all enzymes are proteins but all proteins are not enzymes except ribozymes
Systems Pharmacology as a tool for future therapy development: a feasibility ...Guide to PHARMACOLOGY
Systems pharmacology has the potential to facilitate a novel range of medical interventions. Databases such as the IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, www.guidetopharmacology.org) provide information on drugs and their pharmacological effects. Combining these resources with understanding of biological systems gives us the opportunity to predict, model and quantify the effects of drug administration on whole systems. We can also ask how multiple drugs can be used together in new types of therapies that outperform conventional single target therapies.
Here, we explore the feasibility of undertaking a systems pharmacology analysis of the mevalonate branch of the cholesterol biosynthesis pathway.
Presented by Joanna Sharman at ISMB/ECCB 2015 in Dublin
Similar to Rings In (Candidate) Drugs - Case Stories (20)
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Travis Hills' Endeavors in Minnesota: Fostering Environmental and Economic Pr...Travis Hills MN
Travis Hills of Minnesota developed a method to convert waste into high-value dry fertilizer, significantly enriching soil quality. By providing farmers with a valuable resource derived from waste, Travis Hills helps enhance farm profitability while promoting environmental stewardship. Travis Hills' sustainable practices lead to cost savings and increased revenue for farmers by improving resource efficiency and reducing waste.
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).
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
The ability to recreate computational results with minimal effort and actionable metrics provides a solid foundation for scientific research and software development. When people can replicate an analysis at the touch of a button using open-source software, open data, and methods to assess and compare proposals, it significantly eases verification of results, engagement with a diverse range of contributors, and progress. However, we have yet to fully achieve this; there are still many sociotechnical frictions.
Inspired by David Donoho's vision, this talk aims to revisit the three crucial pillars of frictionless reproducibility (data sharing, code sharing, and competitive challenges) with the perspective of deep software variability.
Our observation is that multiple layers — hardware, operating systems, third-party libraries, software versions, input data, compile-time options, and parameters — are subject to variability that exacerbates frictions but is also essential for achieving robust, generalizable results and fostering innovation. I will first review the literature, providing evidence of how the complex variability interactions across these layers affect qualitative and quantitative software properties, thereby complicating the reproduction and replication of scientific studies in various fields.
I will then present some software engineering and AI techniques that can support the strategic exploration of variability spaces. These include the use of abstractions and models (e.g., feature models), sampling strategies (e.g., uniform, random), cost-effective measurements (e.g., incremental build of software configurations), and dimensionality reduction methods (e.g., transfer learning, feature selection, software debloating).
I will finally argue that deep variability is both the problem and solution of frictionless reproducibility, calling the software science community to develop new methods and tools to manage variability and foster reproducibility in software systems.
Exposé invité Journées Nationales du GDR GPL 2024
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.
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.
1. Rings in (Candidate) Drugs – Case Stories
Jonas Boström, CVMD iMED, AstraZeneca R&D, Mölndal, Sweden
jonas.bostrom@astrazeneca.com
2. A Five Case Story Rollercoaster
key computational approach for designing candidate drugs often the use of shape and electrostatic comparisons between molecules
1) for (purely) geometrical reasons
2) replacing unwanted functional groups (acids and esters)
3) to fine-tune electrostatics for improved properties
2000
CB1
scaffold-hopping –>
only geometry matters 1
LXR
scaffold-hopping
and ”luck” 1
P2Y12
ester replacement
heterocycle 2
NOFI
acid bioisostere –
> heterocycle 2
now
”Matched-Pair
Project X”
heterocyclic electrostatics
improved properties 3
Heterocyclic rings…
4. Rimonabant (Sanofi-Aventis):
a selective high-affinity CB1 inverse agonist
inhibits food intake in rats, mice, marmosets and man
was in clinical studies for treatment of obesity
Cannabis increases food intake Marijuana users are often overweight inverse agonist (or antagonist)?
No CB1 protein X-ray structure ligand-based design
CB1 antagonists – a “me-too” project
Our scaffold-hopping strategy
Replace the pyrazole scaffold in Rimonabant with different heterocyclic rings:
thiazoles, pyrroles and pyrazines
Check chemical feasibility
Check shape-complementarity to the putative bioactive conformation of Rimonabant
Mini-libraries of 20 cpds/class were synthesized to evaluate the different classes.
Boström et al. “Scaffold hopping, synthesis and structure–activity relationships of 5,6-diaryl-pyrazine-2-amide derivatives: A novel series of
CB1 receptor antagonists”. Bioorganic and Medicinal Chemistry, 2007,15, 4077.
5. Shape-Based Scaffold-Hopping
All classes virtually identical to Rimonabant
Shape-overlays (ROCS). Tanimoto> 0.9
All central scaffolds “work”, and are electronically different – essential for geometrical reasons?
(compounds very lipophilic)
AZ-”pyrazines”
AZ-”pyrroles”
AZ-”thiazoles”
19 cpds synthesized
10 < 100nM
(4 < 10nM)
33 cpds synthesized
17 < 100nM
(4 < 10nM)
17 cpds synthesized
4 < 100nM
(2<10nM)
+ from the literature/patents
imidazoles, triazoles, ring-closures, etc
6. Withdrawal of marketing authorization for Rimnabant (FDA/EMEA). AZ Project stopped after candidate drug nomination.
Effect of AZ-”pyrazine” and Rimonabant on body-weight (BW) in cafeteria-diet, obese mice.
Cpd5e
CB1 Summary
AZ-”pyrazine”
AZ-”pyrazine”
any
heterocycle
?
“The function of the central scaffold is not to make any
direct interactions with the cannabinoid receptor, but
rather to place the substituted phenyl rings and the N-
carboxyamide fragments in an optimal 3D orientation”
Boström et al. “Scaffold hopping, synthesis and structure–activity relationships of 5,6-diaryl-pyrazine-2-amide derivatives: A novel series of CB1 receptor antagonists”.
Bioorganic and Medicinal Chemistry, 2007,15, 4077.
8. “T0901317”
24 nM
“AZ HTS hit”
70 nM
A novel series of
potent nonsteroidal
LXR agonists
LXR “Lucky” Scaffold-hopping
Liver X Receptor (LXR) agonists for the treatment of atherosclerotic cardiovascular disease
Conformational ensembles OMEGA, shape-matching ROCS accessed via an interactive web-interface
The design of a novel series LXR agonists from a conformational analysis of two compounds:
Molecular
Alignments
9. LXR Scaffold-hopping
Systematic pair-wise shape comparison of low-energy conformation gave a few alignments
Conformational ensembles OMEGA, shape-matching ROCS accessed via an interactive web-interface
hydrophob
hydrophob
acceptor
acceptor
hydrophob
It seemed to make sense…
Tanimoto: 0.86
add one “H-bond acceptor”
Visual inspection of these favored the alignment which the N-substituted side-chains and the
phenyl rings (pharmacophores/SAR) are all in approximate coincidence.
10. Then came the LXR X-ray structure…
The right geometry (and potency)…but for the wrong reason…
Conformation was essentially correct, but the pose wasn’t
PDB: 1PQC
11. LXR X-ray structures were solved…
isothiazol-3(2H)-one 1,1-dioxides containing scaffold superior to HTS hit series
A novel series of
potent nonsteroidal
LXR agonists
“designed”
17 nM
lucky scaffold
hopping
expansion
virtually
identical
Project stopped after candidate drug nomination
“AZ HTS hit”
70 nM
Boström et al. “Do structurally
similar ligands bind in a similar
fashion?”. J.Med. Chem., 2006,
49, 6716.
13. Easy chemistry – library design
160 cpds with variation of substituents on pyridine and phenyl
SAR – affinity range for compounds binding/GTPgS
Zetterberg, Bach, Boström ”A novel series of piperazinyl-pyridine ureas as antagonists of the purinergic P2Y12 receptor” Bioorg. Med. Chem. Lett. 21 (2011) 2877–2881
SAR
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of
blood through the circulatory system. May cause stroke and sudden death.
HTS several hits
Among the most interesting: the ”piperazinylpyridines” series
P2Y12 – Prevention of Thrombosis
14. Ethyl ester functionality a potential liability
• generally high in vivo clearance due to hydrolysis
P2Y12 – ethylester replacements
Can we replace the ester while retaining activity?
…and increase metabolic stability by replacing the ethyl ester with bioisosteres
15. P2Y12 – ethylester replacements
Non-cyclic ester replacements – inactive in P2Y12 binding and GTPgS
16. Design Strategy
Replace ethylester functionality by hydrolytically stable 5-membered heterocycle
Around 20 five-membered heterocyclic systems synthetically attainable evaluated.
Shape and electrostatics to classify similarity to ethyl ester
Heterocyclic Rings as Ethylester Replacements
“good”
+1
“mediocre”
+4
“bad”
+ a few
Ten compounds (structures shown) made and tested.
Bach, Boström, Zetterberg “5-Alkyl-1,3-oxazole derivatives of 6-amino-nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y12 receptor”
Future Med. Chem., 2013, 5(17), 2037-2056
17. P2Y12 Results
Oxazoles a suitable replacement
shape and electrostatics (ItsElectric*)
* ItsElectric and EON (OpenEye) are based on the same
toolkit (ZAP) and theory (PB electrostatic potentials).
18. correctly suggests that 5-methyl-oxazole better than the 4-methyl oxazole
Conformations where possible ring-substitutents overlayed with the ethyl moiety selected
weak
H-bond
acceptor
strong
H-bond
acceptor
Shape & Electrostatic complementarities
vdW
19. P2Y12 Summary
The potential metabolic instability of ethyl esters was addressed by shape and electrostatics
rankings to select 5-membered heterocycles for synthesis.
Hydrolytically stable 5-methyl derivatives were identified as P2Y12 antagonists.
The physical nature of the shape and electrostatic similarity approach ensured that a non-obvious
substructure change could be incorporated to mimic the behavior of the ethyl ester functionality.
Not likely that other commonly used similarity measures (FPs, MCSS), would have predicted the
oxazole fragment as similar to the ethyl ester, let alone correctly suggesting that the 5-methyl-
oxazole was a better replacement for the ethyl ester than the 4-methyl oxazole.
The levels of clearance and bioavailability made the oxazoles series attractive compounds for
further development.
The ester subseries made it to the clinic – but lack of efficacy
20. …a P2Y12 X-ray structure was published (and PDB deposited) last year
P2Y12 Post-Summary
21. Where’s the H-bond donor?
Ethylester fits tightly, and no room for ”missing” waters.
SER-156 could adopt another rotamer (<4.0Å hbond) to carbonyl oxygen
No interaction for ether oxygen (making sense…)
Electron density quality
P2Y12 Post-Summary
PDB 4ntj
(Resolution 2.6Å)
23. Protein-protein interfaces provide an important class of drug targets receiving increased attention. The
typical design strategy usually involves large molecules (peptides and macrocycles)
A simplistic(!) view
of the mechanism
Novel Oral Fibrinolysis Inhibitors (NOFI)
Boström et al “Potent Fibrinolysis Inhibitor Discovered by Shape and Electrostatic Complementarity to the Drug Tranexamic Acid” J.Med.Chem. 2013, 56, 3273
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic
24. X-ray crystallography – structures known
pdb: 1ceb
(and 1cea)
Crystal structures of the recombinant Kringle 1 domain of human plasminogen in complexes with the
ligands EACA and TXA (Mathews et al. Biochemistry, 1996, 35, 2567–2576)
Fibrinolysis Inhibition
25. Project goal: identify novel compounds which can be given at lower doses and less frequently than
TXA, by improving some combination of the efficacy, bioavailability and clearance.
TXA and EACA are well-established clinical agents used to reduce blood-loss following surgery
and trauma and to treat heavy menstrual bleeding, mild haemophilia and certain forms of von
Willebrands disease
Tranexamic acid (TxA) EACA
Modest potency and non-optimal pharmacokinetic properties leading to inconvenient dosing (up to 6 g
per day). Associated side-effects are also nausea and vomiting.
This clearly limits their use and there is consequently an unmet need for new inhibitors of plasminogen
with a more convenient dosing and a more acceptable side-effect profile.
Lysine analoges:
Two Fibrinolysis Inhibitors on the Market
26. Zooming in on TXA in complex with the
recombinant kringle-1 domain of human
plasminogen …
prominent electrostatic features
zwitterionic...
pdb: 1ceb (TxA)
pdb: 1cea (EACA)
Shape-based approaches often successful in virtual screening. In this case not be sufficiently discriminatory due
to the simple molecular framework of the zwitterion TXA. This motivated us to compare electrostatic potentials
27. Low-throughput screening assay for testing putative blood clotting agents; select a small set of compounds
Shape-based screening not sufficiently discriminatory due to simple molecular framework of TXA
At the time, pre-filtering was a necessity (electrostatic calculations not fast enough)
“De-crapping” and visual inspection
Virtual Screen Strategy
28. Virtual Screening – Results
68 compounds screened – ‘only’ one hit
Remaining compounds selected were either weakly active or inactive.
VS
Clot-Lysis plasma assay 0.8 µMClot-Lysis plasma assay 3.1 µM
The potency of the lead compound 4-PIOL was found to be four times that of TXA, the current drug
widely used in the clinic. Surprising that such an active compound from such as a small set of
measurements was discovered.
29. Isoxazolone a bioisostere
Visual inspection of the hydrogen-bonding network in the ligand−protein complex indicates that 4-
PIOL and TXA bind in their zwitterionic forms (modelled in their neutral state).
The shape of the binding site is well-defined, with both ligands filling the binding site.
isoxazolone as a
carboxylic acid
bioisostere
(~5 times potent)
GABA 33nM
GABA 6nM
* Using ligand-based approach ROCS/EON
isoxazolone
30. ClotLys (Plasma): 0.8µM
pKa acid: 4.0
ClotLys (Plasma): 1.3µM
pKa acid: 4.1
ClotLys (Plasma): 4.0µM
pKa acid: 8.2
ClotLys (Plasma): 6.3µM
pKa acid: 7.0
ClotLys (Plasma): >100µM
pKa acid: 4.0
Tetrazole the most
common carboxylic
acid isostere, but is an
imperfect surrogate.
None more potent
Acquired and/or synthesized
heterocyclic compounds
Few similar compounds to 4-PIOL available internally and externally at the time*
33. DMPK Profiling
The lipophilicity of 4-PIOL was determined to be low (logD < 0), an atypical liability.
Hydrophilicity can be disadvantageous, mainly due to poor cell permeability (Caco-2), resulting in
unfavorable DMPK characteristics in general and suggestive of difficulties with creating a
successful oral formulation
The pKa of the basic amines in TXA and 4- PIOL are similar (9.7 and 10.5), and that
the acid pKa’s are nearly identical (4.1 and 4.0).
34. Summary
• 4-PIOL was identified as a four-fold more potent fibrinolysis inhibitor than TXA using a low
throughput screen where the compound selection was made using computational
techniques.
• The key computational approach to our contribution for finding the right lead compound
was shape and electrostatic comparisons between molecules.
• It is clear that the computational approach described in the present work identified a non-
trivial bioisostere of TXA as a high quality lead for a subsequent lead optimization program.
• It is difficulty to accurately assigning correct ionization states to a large collection of
molecules, supporting our approach of modeling all compounds in their neutral state.
• 4-PIOL served as an excellent starting point for subsequent lead optimization.
35. Analogs to 4-PIOL selective against GABA-A, with good cell permeability and retained potency with respect
to plasminogen inhibition were designed, by means of two approaches, keeping the
graph/framework.
• A “methyl-scanning” exercise on 4-PIOL and
• molecular overlays of two structurally different series
Leading to the same observation:
substitution of the 2’-position increases GABA-A selectivity and improved cell permeability
Lead Optimization
Challenging synthetic chemistry issues were solved
Project stopped after candidate drug nomination.
“4-PIOL served as an excellent starting point for subsequent lead optimization”
* Concerns over commercial value especially after Lysteda (TxA in a sustained slower-release formulation) launch in US.
36. Molecular Matched-Pair Project X
”Matched-Pair Project X”
fine-tune heterocyclic electrostatics
improved properties 3
https://twitter.com/jmedchem background from MMP oxadiazole paper:
Boström et al J. Med. Chem., 2012, 55, 1817
37. • “Molecules that differ only by a small structural change”
(remainder of the molecule is exactly the same).
For example
• The assumption underlying the matched-pair approach is that it is easier to predict
differences in the values of a property than it is to predict the value of the property
itself (one reason is cancellation of errors).
• The observation of an effect across several chemical series increases our confidence
that the effect is real -> general “rules of thumbs” -> future design
• One limitation is that it can only make predictions about structural features that have
precedent in the given assay.
What Are Molecular Matched-Pairs?
Prazosin Terazosin
Solubility: 1.1 mg/ml Solubility: 28.1 mg/ml
38. Oxadiazoles in an in-house AZ project
O
O N
N
R1R2
O
N N
O
R1R2
Binding Affinity: 80 nM
Log D: 3
Solubility: NA
HLM Clint: 20 µl/min/mg
hERG: 2 µM
Binding Affinity: 40 nM
Log D: 2
Solubility: 100 mM
HLM CLint: 10 µl/min/mg
hERG: 10 µM
1,3,4-oxadiazoles showed better properties than 1,2,4-oxadiazoles
in terms of lipophilicity, solubility, HLM Clint and hERG
Goal: to develop a better understanding for the generality of the observed effects, as
well as if possible rationalize the effect.
1,3,4-oxadiazoles1,2,4-oxadiazoles
39. Oxadiazoles
are five-membered heterocycles containing two carbons, two nitrogens and one oxygen atom
and they exist in several different regioisomeric forms
R' O
N N
R''
R' N
O N
R''
R'
N N
O
R''
R' N
N O
R''
1,2,4-oxadiazoles
1,3,4-oxadiazole
1,2,5-oxadiazole
CSD: NAXDIZ
CSD: ZZZTQC01
Side chains (R-groups) will have the same exit vector for 1,2,4 and 1,3,4 regioisomers:
same overall shape
(but the 1,2,5 regioisomers differs)
40. Year
Frequencyofoccurrenceofoxadiazoles
inPharmaceuticalPreparations
Oxadiazoles in drug projects
Oxadiazole rings are used in drug discovery programs for different purposes
• contributing to the binding interactions with the target.
• modulates molecular properties through its position on the periphery of the molecule
• oxadiazoles has been used as replacements for carbonyl containing compounds (esters, carbamates, hydroxamic esters)
• as linker to orient its substituents appropriatly.
N
S
N
H
N
N
O
O
O
O
N
N
OH
ONO
N
F
1 (zibotentan) 2 (ataluren)
Structures of oxadiazole compounds in late stage clinical development or launched
F
N
H
O
N
N
O
OH
N
H
O
NN
O
3 (raltegravir)
41. Oxadiazole data set
Using query-specific matched-pair tool 150 pairs.
The compounds essentially show the same characteristics as compounds with typical drug-like properties.
The data set covers molecules with different ionization states at physological pH;
and several structural series; ~25 clusters. ClogP
H-bond don+acc
MW
42. Check differences in lipophilicity
ordered exp. logD for the 148 matched-pairs
1,3,4-oxadiazole are systematically less lipophilic than their 1,2,4-oxadiazole partner by one log unit
R' O
N N
R''R' N
N O
R''
1,2,4-oxadiazoles 1,3,4-oxadiazole
The median logD value for the 1,2,4-isomers
is 4.4, whereas it is 3.2 for the 1,3,4-isomers.
y = 0.99 + 1.06*x
r2 = 0.97
Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817
43. Matched Pairs Consequences
Lipophilicity is a cardinal property in drug discovery.
It generally affects many other properties relevant in lead optimization.
How would the difference in lipophilicity between the oxadiazole regioisomers
impact other molecular properties?
We investigated for example:
Solubility
hERG (and pKa)
CYP inhibition
HLM CLint
Desiredproperty
Lipophilicity/undesired property
1
2
3
?
44. Impact on solubility (subset of 55 pairs)
Lipophilicity can influence many other molecular properties, and perhaps the most obvious
connection exists between lipophilicity and solubility.
R2=0.4
N=116
In general the 1,3,4-oxadiazole is more soluble
than the 1,2,4-oxadiazole partner
Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817
45. In addition, the 1,3,4-oxadiazoles generally show better metabolic stability, in terms of lower
HLM CLint values (34 matched-pairs).
Impact on CYP inhibition
For various CYP enzymes the inhibitory potency of the less polar 1,2,4-oxadiazole derivatives is typically
more pronounced than that of the more polar 1,3,4-conterparts; this is particularly true for CYP3A4
(recognizing lipophilic substrates) and CYP1A2 (recognizing planar heterocycles).
Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817
46. Inhibition of the hERG channel can trigger Torsades de Pointes and arrhythmia
One design strategy to reduce hERG inhibition is to decrease lipophilicity.
In the majority of cases (N=11), the less lipophilic isomer (1,3,4) is also less potent at hERG.
All matched pairs in this subset have a basic functionality near the oxadiazole unit.
There’s little or no change in pKa upon switching between the regioisomers. That is, the
regioisomers do not have a significant effect on the basicity of the nearby groups.
Impact on hERG
Boström et al ”Oxadiazoles in Medicinal Chemistry” J. Med. Chem., 2012, 55, 1817
47. Using electrostatics to rationalize
Why are 1,3,4-oxadiazole less lipophilic? Ask your MedChemists (none knew) and calculate…
Dipole calculations at B3LYP/6-31G**. Experimental data confirms.
Kenny P. et al. J. Med. Chem. 2008, 51, 3720–3730, and Kenny P J. Chem. Soc. Perkin Trans 2 1994, 199-202
1,3,4-oxadiazole show significantly larger dipoles than their 1,2,4-oxadiazole partner
The greater the dipole the greater polarity.
N
ON
O
N N
Minimized molecular electrostatic potential (Vmin) has been shown to be an effective predictor
of the of hydrogen bond acceptors
- hydrogen bond acceptor strength changes and moves around
48. Other (unexpectedly) large differences
thiadiazole regioisomers
THF vs furan
We have for example investigated:
49. Thiadiazoles regioisomeric pairs
Calculated electrostatics show analogous differences to oxadiazole regioisomers
(3.7 vs 2.5D) although the difference is slightly smaller (3.3 vs 2.6D).
In thiadiazoles the oxadiazole oxygen atom is ‘replaced’ by a sulfur atom
Prediction: a 1:1 relationship between regioisomeric pairs, and that the 1,3,4-
thiadiazoles is less lipophilic than 1,2,4 regioisomers.
N
SN
S
N N
3.3 D
2.6 D
level of theory: HF/3-21G*
exit vectors
differ somewhat
50. 0
1
2
3
4
5
6
7
8
0 1 2 3 4 5 6 7 8
explogD
1,2,4-thiadiazoles
exp logD
1,3,4-thiadiazoles
Differences in lipophilicity
1,3,4-thiadiazole are in general less lipophilic than their 1,2,4-thiadiazole partner
R' S
N N
R''R' N
N S
R''
1,2,4-oxadiazoles 1,3,4-oxadiazole
R2=0.92
logD
The median logD value for the 1,2,4-isomers
is 3.2, whereas it is 2.3 for the 1,3,4-isomers.
N = 33
ordered exp. logD for the 80 compounds
1,2,4-thiadiazoles 1,3,4-thiadiazoles
51. Alpha-blocker
Solubility: 1.1 mg/ml
Log D (shake-flask): 1.8
ACDlogD: 0.0
clogP: 2.0
Alpha-blocker
Solubility: 28.1 mg/ml
Log D (shake-flask): 0.9
ACDlogD: -1.0
clogP: 2.2
A “me-too” observation: furan vs THF
Modification of the hybridization state of carbon atoms can be useful to control molecular properties.
Prazosin (Minipress™) – Terazosin (Hytrin™) serves as a matched-pair “me-too” example.*
* Water solubility for Terazosin increases significantly when going from furan to THF. As a result, improved
bioavailability (90% vs 57%) and half-life (2–3 times) afford longer duration of action, and allow once-daily
administration. In addition, there is a safety concern associated with furans, since they are often anticipated to be
carcinogentic in humans.
Giordanetto, Boström and Tyrchan “Follow-on drugs: how far should chemists look?” Drug Discovery Today, 2011, 16 (15-16),722-732. (doi:10.1016/j.drudis.2011.05.011)
Prazosin
US Reg Date: 1976-06-23
Terazosin
US Reg Date: 1987-08-07
52. Furan vs tetrahydrofurans: Dsolubility
average pSolubility: 4.0 (100µM)average pSolubility: 4.7 (20µM)
D pSol: 0.7
A data set of 50 matched-pairs – measure aqueous solubility for the 100 compounds
The THF containing compound is more soluble in 85% of the matched-pairs.
THF
pSolubility
pSolubility (furan)
The observered difference in solublity for furan/THF pairs seems to be general.
R R
53. Possible rationale for differences
Larger dipole for THF than furan – the greater the dipole the greater polarity.
The aromaticity in furan obviously makes it different from ethers, especially compared to more strained systems like oxatanes and
tetrahydrofurans. Consequently tetrahydrofurans seem to be less lipophilic than their open-chain ether partners.
Furan:
0.6 Debye
THF:
1.7 Debye
FURAOX LIBVIC
Different geometries – “escaping flatland”
two matched-pairs found in CSD
A forgotten furan-bioisoster? Furan-to-Thiophene/Benzene is way more frequent than furan-to-THF.
54. Matched-Pairs Summary
It can be very powerful to use molecular matched-pairs in drug design.
• Intuitive, interpretable and can provide data-driven, interpretable guidelines for design/analysis
• Can extract tacit knowledge from accumulated data beyond series, projects and departments
Analyzing 1,2,4- and 1,3,4-oxadiazole regioisomers revealed systematic trends
the 1,3,4-oxadiazole isomer show an order of magnitude of lower logD, compared to the 1,2,4
the favorable effect is also observed in increased aqueous solubility, lower HLM Clint and hERG.
The distinct profile difference is likely due to their different charge distributions.
Methodology can be used to generalize other important properties used for decision-making.
thiadiazoles regioisomers, THF vs furan.
direct impact in in-house AZ projects.
55. Thanks to all my colleagues!
key computational approach for designing candidate drugs often the use of shape and electrostatic comparisons between molecules
1) for (purely) geometrical reasons
2) replacing unwanted functional groups (acids and esters)
3) to fine-tune electrostatics for improved properties
2000
CB1
scaffold-hopping –>
only geometry matters 1
LXR
scaffold-hopping
and ”luck” 1
P2Y12
ester replacement
heterocycle 2
NOFI
acid bioisostere –
> heterocycle 2
now
”Matched-Pair
Project X”
heterocyclic electrostatics
improved properties 3
Heterocyclic systems needs special attention – a large number of combinations