With the passage of time, PROTACs technology has entered an unprecedented stage of development in recent years. Scientists gradually see the absolute advantages of this technology, which can not only transform non-drug target (undruggable) into feasible drug target (druggable) but also resolve the problem of drug resistance of existing targets. In recent years, we have made great efforts to develop the (PROTAC) platform of protein degradation technology to provide research tools for small molecules targeting so-called non-proprietary drugs, in order to better help customers and help customers in the process of new drug research and development. According to the different requirements of customers, BOC Sciences can design, synthesize, optimize PROTAC molecules, establish analytical methods and carry out the biological evaluation.
PROTAC Technology: An Effective Targeted Protein Degrader.pdfDoriaFang
PROTACs are heterofunctional small molecules consisting of two ligands linked by an appropriate linker: one ligand recruits and binds the protein of interest (POI), while the other recruits and binds the E3 ubiquitin ligase.
PROTAC Technology in Tumor Targeted Therapy - Creative BiolabsCreative-Biolabs
Today, we will explore the protac technology applied in tumor-targeted therapy. The following will be presented to you, such as a brief introduction to Protac, the mechanism of action, the advantages and disadvantages of protac as a drug, and the core content: the application of protac technology in tumor therapy. And the last part, the protac solutions provided by Creative Biolabs. If you have any questions about the PROCT development, please email us.
Email: info@creative-biolabs.com
Summary of PROTAC Degraders in Clinical Trials.pdfDoriaFang
A major class of molecules that may enable such proteins to be modulated through TPD are known as proteolysis-targeting chimera (PROTAC) protein degraders. Here we talk about the summary of PROTAC degraders in clinical trials.
Molecular Mechanics in Molecular ModelingAkshay Kank
In this slide you learn about the computational chemistry and its role in designing a drug molecule. Also learn concept about the molecular mechanics and its application to Computer Aided Drug Design. difference between the Quantum mechanics and Molecular Mechanics.
Summary of PROTAC And Other Targeted Protein Degradation Technologies.pdfDoriaFang
We summarize various targeted degradation strategies and their respective advantages and disadvantages, hoping to provide guidance value for the development of targeted protein degradation drugs.
PROTAC Technology: An Effective Targeted Protein Degrader.pdfDoriaFang
PROTACs are heterofunctional small molecules consisting of two ligands linked by an appropriate linker: one ligand recruits and binds the protein of interest (POI), while the other recruits and binds the E3 ubiquitin ligase.
PROTAC Technology in Tumor Targeted Therapy - Creative BiolabsCreative-Biolabs
Today, we will explore the protac technology applied in tumor-targeted therapy. The following will be presented to you, such as a brief introduction to Protac, the mechanism of action, the advantages and disadvantages of protac as a drug, and the core content: the application of protac technology in tumor therapy. And the last part, the protac solutions provided by Creative Biolabs. If you have any questions about the PROCT development, please email us.
Email: info@creative-biolabs.com
Summary of PROTAC Degraders in Clinical Trials.pdfDoriaFang
A major class of molecules that may enable such proteins to be modulated through TPD are known as proteolysis-targeting chimera (PROTAC) protein degraders. Here we talk about the summary of PROTAC degraders in clinical trials.
Molecular Mechanics in Molecular ModelingAkshay Kank
In this slide you learn about the computational chemistry and its role in designing a drug molecule. Also learn concept about the molecular mechanics and its application to Computer Aided Drug Design. difference between the Quantum mechanics and Molecular Mechanics.
Summary of PROTAC And Other Targeted Protein Degradation Technologies.pdfDoriaFang
We summarize various targeted degradation strategies and their respective advantages and disadvantages, hoping to provide guidance value for the development of targeted protein degradation drugs.
CADD UNIT V - Molecular Modeling: Introduction to molecular mechanics and quantum mechanics.Energy Minimization methods and Conformational Analysis, global conformational minima determination.
Drug discovery take years to decade for discovering a new drug and very costly
Effort to cut down the research timeline and cost by reducing wet-lab experiment use computer modeling
Others have done the work. Some have used the work. I have spoken only on behalf of their behalf.
Drug and Chemical Databases 2018 - Drug DiscoveryGirinath Pillai
Latest collection of Chemical and Drug Databases for Biological Research as well as Drug Design studies. Databases statistics, links and overview data with CADD introduction.
CONCEPT OF PHARMACOPHORE
PHARMACOPHORE MAPPING
IDENTIFICATION OF PHARMACOPHORE FEATURE
CONFORMATIONAL SEARCH
INSILICO DRUG DESIGN
VIRTUAL SCREENING
PHARMACOPHORE BASED SCREENING
First introduced by Paul Heritich in 1990
A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule.
It is the key features responsible for an activity (eg. Substrates, inhibitors)
A pharmacophore is a representation of generalized molecular features including;
3D (hydrophobic group, chaeged /ionisable group, hydrogen bond donar/ acceptor)
2D (substructure)
1D (physical & biological)
Pharmacophore Mapping is the definition and placement of pharmacophoric features and the alignment techniques used to overlay 3D.
Two somewhat distinct usages:
That substructure of a molecule that is responsible for its pharmacological activity (c.f. chromophore)
A set of geometrical constraints between specific functional groups that enable the molecule to have biological activity
The process of deriving pharmacophore is known as pharmacophore mapping.
Quantitative structure - activity relationship (QSAR)
Why QSAR?
costs – 800M$ to bring a new drug to market
Patent life time is limited (generic drugs)
Synthesis / Purification of compounds is expensive and time consume-able
It is like find a needle in the haystack
QSAR helps for focusing most promising drug candidates
QSAR is a mathematical relationship between a “biological activity of a molecular system” and its “geometric and chemical characteristics”.
Such relationships holds – Equations can be drawn up- some confidence
to which should be Fit to the target
QSAR what actually do?
IDENTIFY AND QUANTIFY the Physico-chemical properties effect on Drug’s Biological activity
Aims
To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula
Requirements
Quantitative measurements for biological and physicochemical properties
Physicochemical Properties
Hydrophobicity of the molecule
Hydrophobicity of substituents
Electronic properties of substituents
Steric properties of substituents
QSAR equations are only applicable to compounds in the same structural class (e.g. ethers)
However, log Po is similar for anaesthetics of different structural classes (ca. 2.3)
Structures with log P ca. 2.3 enter the CNS easily
(e.g. potent barbiturates have a log P of approximately 2.0)
Can alter log P value of drugs away from 2.0 to avoid CNS side effects
Physical properties are measured for the molecule as a whole
Properties are calculated using computer software
No experimental constants or measurements are involved
Properties are known as ‘Fields’
Steric field - defines the size and shape of the molecule
Electrostatic field - defines electron rich/poor regions of molecule
Hydrophobic properties are relatively unimportant
No reliance on experimental values
Can be applied to molecules with unusual substituents
Not restricted to molecules of the same structural class
Predictive capability
Comparative molecular field analysis (CoMFA) - Tripos
Build each molecule using modelling software
Identify the active conformation for each molecule
Identify the pharmacophore
THANKING YOU
PRESENTED BY: HARSHPAL SINGH WAHI, SHIKHA D. POPALI
USEFUL FOR PHARMACY STUDENTS AND ACADEMICS, INDUSTRIALS FOR MOLECULE DEVELOPMENT, MODELING, DRUG DISCOVERY, COMPUTATIONAL TOOLS, MOLECULAR DOCKING ITS TYPES, FACTORS AFFECTING, DIFFERENT STAGES, QSAR ADVANTAGES, NEED
CADD UNIT V - Molecular Modeling: Introduction to molecular mechanics and quantum mechanics.Energy Minimization methods and Conformational Analysis, global conformational minima determination.
Drug discovery take years to decade for discovering a new drug and very costly
Effort to cut down the research timeline and cost by reducing wet-lab experiment use computer modeling
Others have done the work. Some have used the work. I have spoken only on behalf of their behalf.
Drug and Chemical Databases 2018 - Drug DiscoveryGirinath Pillai
Latest collection of Chemical and Drug Databases for Biological Research as well as Drug Design studies. Databases statistics, links and overview data with CADD introduction.
CONCEPT OF PHARMACOPHORE
PHARMACOPHORE MAPPING
IDENTIFICATION OF PHARMACOPHORE FEATURE
CONFORMATIONAL SEARCH
INSILICO DRUG DESIGN
VIRTUAL SCREENING
PHARMACOPHORE BASED SCREENING
First introduced by Paul Heritich in 1990
A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule.
It is the key features responsible for an activity (eg. Substrates, inhibitors)
A pharmacophore is a representation of generalized molecular features including;
3D (hydrophobic group, chaeged /ionisable group, hydrogen bond donar/ acceptor)
2D (substructure)
1D (physical & biological)
Pharmacophore Mapping is the definition and placement of pharmacophoric features and the alignment techniques used to overlay 3D.
Two somewhat distinct usages:
That substructure of a molecule that is responsible for its pharmacological activity (c.f. chromophore)
A set of geometrical constraints between specific functional groups that enable the molecule to have biological activity
The process of deriving pharmacophore is known as pharmacophore mapping.
Quantitative structure - activity relationship (QSAR)
Why QSAR?
costs – 800M$ to bring a new drug to market
Patent life time is limited (generic drugs)
Synthesis / Purification of compounds is expensive and time consume-able
It is like find a needle in the haystack
QSAR helps for focusing most promising drug candidates
QSAR is a mathematical relationship between a “biological activity of a molecular system” and its “geometric and chemical characteristics”.
Such relationships holds – Equations can be drawn up- some confidence
to which should be Fit to the target
QSAR what actually do?
IDENTIFY AND QUANTIFY the Physico-chemical properties effect on Drug’s Biological activity
Aims
To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula
Requirements
Quantitative measurements for biological and physicochemical properties
Physicochemical Properties
Hydrophobicity of the molecule
Hydrophobicity of substituents
Electronic properties of substituents
Steric properties of substituents
QSAR equations are only applicable to compounds in the same structural class (e.g. ethers)
However, log Po is similar for anaesthetics of different structural classes (ca. 2.3)
Structures with log P ca. 2.3 enter the CNS easily
(e.g. potent barbiturates have a log P of approximately 2.0)
Can alter log P value of drugs away from 2.0 to avoid CNS side effects
Physical properties are measured for the molecule as a whole
Properties are calculated using computer software
No experimental constants or measurements are involved
Properties are known as ‘Fields’
Steric field - defines the size and shape of the molecule
Electrostatic field - defines electron rich/poor regions of molecule
Hydrophobic properties are relatively unimportant
No reliance on experimental values
Can be applied to molecules with unusual substituents
Not restricted to molecules of the same structural class
Predictive capability
Comparative molecular field analysis (CoMFA) - Tripos
Build each molecule using modelling software
Identify the active conformation for each molecule
Identify the pharmacophore
THANKING YOU
PRESENTED BY: HARSHPAL SINGH WAHI, SHIKHA D. POPALI
USEFUL FOR PHARMACY STUDENTS AND ACADEMICS, INDUSTRIALS FOR MOLECULE DEVELOPMENT, MODELING, DRUG DISCOVERY, COMPUTATIONAL TOOLS, MOLECULAR DOCKING ITS TYPES, FACTORS AFFECTING, DIFFERENT STAGES, QSAR ADVANTAGES, NEED
Drug induced hepatotoxicity and its regulatory implicationsChander K Negi
Drug induced hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage. Liver injury may be produced by a large variety of chemical substances The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents Certain medicinal agents, when taken in overdoses & sometimes even when introduced within therapeutic ranges may injure the liver It might not be the drug that cause hepatotoxicity but its metabolite might The herbal drugs and agents can also cause the liver injury
In recent years, the approval of nucleic acid therapeutics for listing has been accelerating. Numerous nucleic acid therapeutics that have the potential to become blockbuster drugs have released clinical data covering cardiovascular and metabolic diseases, liver diseases, and a variety of rare diseases. Especially after the approval of the two mRNA COVID-19 vaccines, nucleic acid therapeutics have received more and more attention from the world.
Prota cs and targeted protein degradationDoriaFang
PROTACs (proteolysis targeting chimera) induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises, and biotechnology companies. PROTACs opened a new chapter for novel drug development.
genes addiion\deeion\ediionthat lead to a therapeutic, prophylactic or diagnostic effect
Plasmid DNA
•Viral vectors
•Genetically engineered micro-organisms
•Human gene-editing technology
•Patient-derived cellular gene therapy products
Future trends and perspectives in modern pharmaceutical biotechnologyinemet
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
Bioanalytical support plays a vital role during the lead optimization stages. The major goal of the bioanalysis is to assess the over-all ADME characteristics of the NCEs and biologics. Bioanalytical tools can play a significant role and impact the progress in drug discovery and development. Dramatic increases in investments in new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and ADC, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME and PK properties.https://www.medicilon.com/blog/featured-stories/dmpk-bioanalysis/
Today around 47 million people survive with dementia, globally. This number is projected to increase to more than 131 million by 2050. About 2.1 million Alzheimer's patients having age of 85 years or older were reported in year 2017.
Several Types of PROTACs Based On Nucleic AcidsDoriaFang
So far, more than 10 nucleic acid drugs have been approved for marketing worldwide, and many nucleic acid drugs are in the stage of clinical trials. Nucleic acid drugs are expected to become the third type of drugs after small molecule drugs and antibody drugs.
Molecular Mechanisms of Neurodegeneration: Neurodegenerative Disorders Webin...QIAGEN
Common molecular mechanisms and pathways leading to neurodegeneration, such as Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease or Multiple Sclerosis, are presented in this slideshow. Learn more about research and therapeutic strategies as well as how these discoveries and tools can be used to facilitate your neurodegeneration research.
Immunotherapy, a type of cancer treatment designed to eradicate disseminated cancer by harnessing the potential of the immune system. Immunotherapy agents do not directly attack the tumour but instead mobilize the immune system -this can be achieved through various approaches that utilize adaptive or innate immunity. The main types of immunotherapy can be broadly subdivided into non-antigen-specific and antigen-specific categories. Non-antigen-specific strategies include nonspecific immune stimulation and Immune checkpoint inhibitors, whereas antigen-specific strategies include adoptive cell transfer of autologous cancer-specific T cells and various therapeutic vaccination approaches.
Computer-aided drug design (CADD) is a widely used technology using computational tools and resources for the storage, management, analysis and modeling of compounds. It relies on digital repositories for study of designing compounds with physicochemical characteristics, predicting whether a given molecule will be combined with the target, and if so how strongly. Computer based methods can help us to search new hits in drug discovery, screen many irrelevant compounds at the same time and study the structure-activity relationship of drug molecules.
In fact, many of the drugs available today contain active ingredients extracted from natural products. Since 1994, nearly half of all drugs were discovered using natural products. Furthermore, between 2005 and 2007, there were 13 new drugs based on natural products that entered the commercial market, including the following 5 new products: small molecule ixabepilone, retapamulin, trabectedin, and the peptides exenatide and ziconotide. Clearly, natural product drug discovery programs continue to play a significant role in the clinical development of new therapies in the biopharmaceutical industry.
A simplified definition of autophagy is that it is an exceedingly complex process which degrades modifed, superfluous (surplus), or damaged cellular macromolecules and whole organelles using hydrolytic enzymes in the lysosomes. Autophagy can be defined in more detail as a regulated process of degradation and recycling of cellular constituents participating in organelle turnover, resulting in the bioenergetic management of starvation.
Dna encoded library technology-boc sciencesBOC-Sciences
DNA encoded library (DEL) is a new screening platform commonly used to discover small-molecules that interfere with the activity of pharmaceutically relevant proteins. DNA-encoded chemical libraries are hybrid-type collections of combinatorial organic molecules, individually coupled to distinctive DNA fragments.
The inhibition and function of heat shock protein 90BOC-Sciences
Hsp90, short for heat shock protein 90, is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signaling proteins. In addition to other molecules involved in cell cycle regulation and immune responses. It supports for the appropriately folding of other proteins, offers help in protein degradation and also stabilizes some proteins needed for tumor growth.
Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer. The main types of immunotherapy now being used to treat cancer include: Immune checkpoint inhibitors, Monoclonal antibodies, Cancer vaccines and Nonspecific immune stimulation.
Antibody-drug conjugates (ADCs) are a very important class of highly potent drugs designed as a targeted therapy for the treatment of people who has cancer. It represents an innovative therapeutic application that includes the unique, high specificity and antitumor activity of monoclonal antibodies which are tumor-specific but not very cytotoxic, with the cell killing activity of small molecule drugs that are too toxic to be used on their own. Scientists could optimize the features of both components by linking monoclonal antibodies with cytotoxic agents.
A coupling reaction in organic chemistry is a general term for a variety of reactions where two hydrocarbon fragments are coupled with the aid of a metal catalyst. Now, we talk about several coupling reactions include (not exhaustive): Wurtz reaction, Glaser coupling, Ullmann reaction, Grignard reaction, Heck reaction, Sonogashira coupling, Stille reaction and Suzuki reaction.
Diabetes describes a group of metabolic diseases in which the person has high blood glucose levels over a prolonged period. Here, we sort out the recent research of diabetes.
New drugs for treating multiple types of cancers boc sciencesBOC-Sciences
Recently, at the annual meeting of the American Society of Clinical Oncology at the United States in 2017, researchers from multinational reported and exchanged their latest study results, the most noteworthy of which was the development of new drugs for the treatment of multiple types of cancers. Here, we sort out about this.
Recent advances of alzheimer's disease boc sciencesBOC-Sciences
Alzheimer's is a type of dementia that causes problems with memory, thinking and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks. Here, we sort out the recent advences of Alzheimer's Disease.
The Herpes virus family includes 8 different enveloped DNA-containing viruses that only affect human beings. The viruses are known by numbers as human herpes virus 1 through 8.
Hypertension is defined as a systolic blood pressure equal to or greater than 140 mmHg or a diastolic blood pressure greater than 90 mmHg. Systolic pressure indicates the force of the blood in the arteries as the heart beats. Diastolic pressure is the force of blood in the arteries as the heart relaxes. There are several classes of antihypertensive medications including thiazide-type diuretics, angiotensin-converting enzymes (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, renin inhibitors, and calcium channel blockers.
Hypotheses and Research of Alzheimer's disease-BOC SciencesBOC-Sciences
There are numerous hypotheses regarding Alzheimer's disease's pathogenesis including formation and metabolic disorders of amyloid-β, cholinergic hypothesis, abnormal Tau protein phosphorylation, the metal ions hypothesis, the involvement of oxidative stress, and others. There are several important targets under research about Alzheimer's disease. They are β-secretase, γ-secretase, Tau, Amyloid-βand Microtubule/Tubulin. BOC Sciences has directed sincere efforts toward providing customers with high quality small molecule reagents for Alzheimer's disease research.
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
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.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
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/
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
This pdf is about the Schizophrenia.
For more details visit on YouTube; @SELF-EXPLANATORY;
https://www.youtube.com/channel/UCAiarMZDNhe1A3Rnpr_WkzA/videos
Thanks...!
3. Traditional drug research and development is
mainly focused on directly regulating the activity
of proteins or enzymes to treat diseases. The
development and application of protein activity
regulators, especially inhibitors, has always
been the mainstream direction of drug research
and development. Nucleic acid-based strategies
that control protein function by affecting protein
expression have recently made a breakthrough.
However, the poor metabolic stability and low
bioavailability limit the wide application of small
molecular nucleic acid technology.
Mechanism
PROTACs-induced targeted protein
degradation has emerged as a novel
therapeutic strategy in drug development.
Background
4. Protein degradation targeting chimera (PROTAC)
technology was derived from the Nobel Prize in the
category of Chemistry. On October 6, 2004, the
Royal Swedish Academy of Sciences announced
that the Nobel Prize in Chemistry would be awarded
to Israeli scientists Aaron Ciechanover, Avram
Hershko and American scientist Irwin Rose, for their
joint discovery of ubiquitin (Ub) regulated protein
degradation.
Background
5. PROTACs are heterobifunctional molecules, which
contain a small molecule targeting the protein of
interest (warhead), a small molecule capable of
recruiting an E3 ligase (E3 ligand), and a linker
connecting the above two moieties.
Introduction
6. The Ubiquitin itself consists of 76 amino acid residues
with a molecular weight of about 8.5 kDa. The name
"ubiquitin" is because it has a highly conserved
sequence and exists in all known eukaryotes. Ubiquitin
actually contains eight different amino acid residues
and can form complex polyubiquitin chains on the
target protein.
Ubiquitin and Ubiquitination
Ubiquitination refers to the process that ubiquitin
molecules classify intracellular proteins, select target
protein molecules, specifically modify target proteins and
form target protein polyubiquitin chains under the action of
a series of special enzymes. These special enzymes
include ubiquitin activating enzyme (E1), ubiquitin binding
enzyme (E2), ubiquitin ligase (E3) and so on.
7. Protacs achieve degradation through "hijacking" the cell's Ubiquitin–Proteosome system (UPS). The UPS
consists of an E1 activating enzyme which conjugates to an E2 enzyme transferring a ubiquitin molecule to
the E2. E2 then binds to the E3 ligase in a complex which can then recognize target proteins for
subsequent ubiquitin tagging and degradation by the 26S proteosome.
Mechanism
PROTACs-induced targeted protein
degradation has emerged as a novel
therapeutic strategy in drug development.
Mechanism
8. Traditional Drugs PROTAC Degraders
Active site required Active site not required
Transient and less durable Sustained degradation
Higher drug exposures required Lower doses for potent degradation
Strong binding required Weak binding is sufficient
Target of 1 function Target of all functions
Isoform non-specific lsoform specific
Inhibition of a subunit Degradation of a complex
Degradation vs Inhibition
10. This PROTAC is composed of a short peptide that binds to E3 ubiquitin ligase and a small molecular that
binds to target protein, respectively, followed by polyubiquitination and proteasome degradation of target
Mechanism
PROTACs-induced targeted protein
degradation has emerged as a novel
therapeutic strategy in drug development.
PEPTIDE-BASED PROTAC TECHNOLOGY
DOI: 10.1002 / cbf.3369
11. This proteolysis targeting chimera (PROTAC) consists of a ligand on an E3 ubiquitin ligase, a linker, and a
ligand on targeted protein
Mechanism
PROTACs-induced targeted protein
degradation has emerged as a novel
therapeutic strategy in drug development.
Small molecule-BASED PROTAC TECHNOLOGY
DOI: 10.1002 / cbf.3369
15. The chart highlights the various steps involved from administration to intracellular degradation and the
biophysical techniques used to study them. In bold are common parameters to characterize PROTACs at
each stage.
The process of
PROTAC
development
Challenge
16. Traditional approaches
inefficient and prone to
artifacts
Rapid and faithful PROTAC
screening system not available
Only couple of ligases
are used as vehicle for
PROTACs
Many undruggable targets are
unPROTACtable due to lack of
ligases and rapid screening
Challenges with PROTAC
Miss toxicity and its detection,
especially long-term toxicity
and reproductive toxicity.
17. Key Questions To Consider When Developing Protein Degraders
PROTACs
Is my PROTAC
cell permeable?
Does my PROTAC form
a ternary complex with
its target and the E3
recruiter?
Active E3 Complex
Does my target
become ubiquinated?
Is my target recruited
to the proteasome?
Is my target
degraded?
UbiquitinTarget E3 Recruiter
E3
18. 01
03
05
02
04
06
Design of the
Ligase System
BOC Sciences's Complete Solution for PROTACs & Targeted Protein Degradation
Target Protein
Services
Structures and
Mechanisms of
PROTAC
PROTAC In Vivo
Evaluation
PROTAC Design
Services
PROTAC In Vitro
Evaluation
19. 01
03
05
02
04
06
E3 Ligase Ligand-Linker
Conjugate
BOC Sciences's PROTACs Related Products
Ligand for E3 Ligase
PROTAC
SNIPER
Ligand for Target Protein
PROTAC Linker
07
09
11
08
10
Ubiquitin Ligases Assay Kit
TargetsPROTAC in Vivo Evaluation
Molecular Glue