The document discusses the process of drug discovery, including target selection, lead discovery, medicinal chemistry, and clinical trials. Target selection involves identifying cellular or genetic targets involved in disease through techniques like genomics, proteomics, and bioinformatics. Lead discovery focuses on identifying small molecule modulators of protein function through methods like synthesis, combinatorial chemistry, and high-throughput screening. Medicinal chemistry then works to optimize these leads through approaches such as structure-activity relationship studies. Compounds then progress to in vitro and in vivo testing before entering clinical trials.
Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices/
Speaker: Mike Watson. Exec Director Drug Development Services, Ricerca BioSciences
Roles and Responsibilities in Clinical Trials of Investigator, Study Coordinator, Sponsor, Monitor, a Contract research organization.
The clinical trial, definition, description, Different types of clinical trials, phases of clinical trial.
The clinical trial study team.
Requirements of the clinical trial study team.
Clinical research team role.
GCP- Good clinical practices.
A presentation outlining the various processes a chemical compound undergoes (thorough & rigorous screening procedures) before it is finally introduced into the drug market
Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices/
Speaker: Mike Watson. Exec Director Drug Development Services, Ricerca BioSciences
Roles and Responsibilities in Clinical Trials of Investigator, Study Coordinator, Sponsor, Monitor, a Contract research organization.
The clinical trial, definition, description, Different types of clinical trials, phases of clinical trial.
The clinical trial study team.
Requirements of the clinical trial study team.
Clinical research team role.
GCP- Good clinical practices.
A presentation outlining the various processes a chemical compound undergoes (thorough & rigorous screening procedures) before it is finally introduced into the drug market
Assignment on Regulatory Prespectives of Clinical TrialsDeepak Kumar
Assignment on Origin and Principles of International Conference on Harmonization - Good Clinical Practice, (ICH-GCP) guidelines Ethical Committee- Institutional Review Board, Ethical Guidelines for Biomedical Research and Human Participant-Schedule Y, ICMR
Origin and principles of international conference on harmonization- Good clin...AbhishekJoshi312
The ppt gives a basic information about ICH-GCP, how it originated , what led to the formation of ICH-GCP guidelines and what are the principles of the guidelines.
Roles and Responsibilities of sponsor in conducting clinical trials as per GC...Dr B Naga Raju
Presentation on Roles and Responsibilities of sponsor in conducting clinical trials as per GCP-ICH for pursuing a subject in the course of PharmD programme under RGUHS
Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug
Drug development is considered as a series of well defined steps, culminating, if successful, in market authorization, of the drug
An introduction for those who may be interested in a career in clinical research, but need to understand the industry and their potential for a role in it.
Provides an overview of the later stages of drug development, explaining the phases of drug studies and explores in brief the key roles for those participating.
Concept of Pharmacovigilance, history and development of pharmacovigilance, WHO International drug monitoring programme, Pharmacovigilance programme of India
Assignment on Regulatory Prespectives of Clinical TrialsDeepak Kumar
Assignment on Origin and Principles of International Conference on Harmonization - Good Clinical Practice, (ICH-GCP) guidelines Ethical Committee- Institutional Review Board, Ethical Guidelines for Biomedical Research and Human Participant-Schedule Y, ICMR
Origin and principles of international conference on harmonization- Good clin...AbhishekJoshi312
The ppt gives a basic information about ICH-GCP, how it originated , what led to the formation of ICH-GCP guidelines and what are the principles of the guidelines.
Roles and Responsibilities of sponsor in conducting clinical trials as per GC...Dr B Naga Raju
Presentation on Roles and Responsibilities of sponsor in conducting clinical trials as per GCP-ICH for pursuing a subject in the course of PharmD programme under RGUHS
Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug
Drug development is considered as a series of well defined steps, culminating, if successful, in market authorization, of the drug
An introduction for those who may be interested in a career in clinical research, but need to understand the industry and their potential for a role in it.
Provides an overview of the later stages of drug development, explaining the phases of drug studies and explores in brief the key roles for those participating.
Concept of Pharmacovigilance, history and development of pharmacovigilance, WHO International drug monitoring programme, Pharmacovigilance programme of India
ANTHONY MELVIN CRASTO, Navi mumbai India, HELPING MILLIONS WITH WEBSITES, Do not discriminate, you will pump jetfeul into the flight of dreams.
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Here is a short summary of collateral we created for product launch and campaign we managed to create awareness and promote product USP.
What is IP, Patents in Pharma Industry by Dr Anthony Crasto, a complete guide for patenting in drug synthesis, discovery, process, polymorphs, AN INSIGHT INTO PCT, DATES, CLAIMS, DEFINITIONS ETC, all you want to know about criteria, method mode, advantages etc, EMAIL ME amcrasto@gmail.com, call +91 9323115463
This lecture outlines the different strategies for finding a fragment hit and the subsequent elaboration strategies used in order to increase potency to develop a lead compound in drug discovery.
4th International Conference on Biomarkers & Clinical Research, will be organized around the theme "Impact of Biomarker Developments in Health Diagnostics and Clinical Research."
The basic aspects of drug discovery starts from target discovery and validation further going to lead identification and optimization. In this particular slide discussion is regarding the target discovery and the tools that have been utilized in this process.
PRINCIPLES OF DRUG DISCOVERY & DEVELOPMENT.pptxDharaMehta45
Principles of Drug Discovery & Development
Presented by…
Name – Dhara Mehta
Subject – PDTT
UNIT - 1
CONTENTS
Introduction
01
What is a "new drug"?....(CDSCO)
Phases
1) Target Identification
Target Identification Tools
• Animal models
• Biomarkers
• Expression Profile
• Cell-line
• Data banks
Properties of Ideal Target
Target Identification Strategies
• Gene Expression profiling: Genomics
• Focussed Proteomics
• Metabolic pathways analysis: MolecularBiology
• Phenotype analysis
• Genetic association
Target identification strategies
• Inverse Docking: It is a computational docking program in which a specific small molecule of interest is tested against a library of receptor structures.
• Bio informatics: It derives knowledge from computational analysis of biological data. It includes information stored in genetic code, patients statistics and scientific literature.
Limitation
• Drugs which do not act through receptors- Antacids, Osmotic diuretics, Alkylating agents, Psoralens and Activated charcoal can not be recognised
Target Validation
Hit Identification
Source of Lead
Source of leads: Animal
Source of leads: Microrganisms
Lead Generation Techniques
Molecular Modeling
Biotechnology
Genetic medicine
Immunopharmacology
SCREENING
Desired Characteristics of the Assay
Virtual screening (VS)
Target based virtual screening (TBVS
Ligand based virtual screening (LBVS).
Lipinski Rule of Five
• Poor absorption or permeation are more likely when there are:
1) More than 5 H-bond donors
2) The molecular weight is over 500
3) The CLog P is over 5 (or MLOGP is over 4.15)
4) The sum of N's and O's is over 10
• Substrates for transporters and natural products are exceptions.
Ligand based virtual screening (LBVS)
HIGH THROUGH PUT SCREENING (HTS)
The Real Screening
It is the process of testing a large number of diverse chemical structures against disease targets to identify "hits".
• Compared to traditional screening methods, HTS is characterised by:
• 1. Simplicity
• 2. Rapidness
• 3. High information harvest
• 4. Based on ligand-target interaction principle
HIGH THROUGH PUT SCREENING...
End results of screens:
Lead Optimization
Lead Optimisation
Lead Optimisation...Various steps:
• 1. Identification of the Pharmacophore (relevant groups on a molecule that interact with a receptor and are responsible for the biological activity
• 2. Functional group modification:Modification of the group may enable or disable certain biological effects.
• 3. S.A.R
Quantitative structure-activity relationships (QSAR-rational drug design)
6. Molecular graphics-based drug design
• To find a structure match, a computer technology called DOCKING is used.
• It is the computer-assisted movement of a terminal-displayed molecule into its receptor.
• Docking algorithms deal with ligand conformation prediction and orientation within the target active site.
• It predicts the various forces acting between target and ligand.Scoring function is a mathematical
WE THE STUDENT OF PHARMACEUTICAL CHEMISTRY FROM GURUNANAK COLLEGE OF PHARMACY HAS PRESENTED QSRR, TO MAKE READERS EASILY AVAILABLE, A COMPLETE TOPIC OF MPHARM 1ST YEAR WHICH WILL MAKE THEIR STUDY AND TO COLLECT DATA MORE EASILY AT A PLACE.
Provide statistical and computational tools for biologically based activities such as genetic analysis, measurement of gene expression, and gene function determination. Develop software or applications for scientific or technical use.
INTRODUCTION
A PERFECT THERAPEUTIC DRUG
DRUG DISCOVERY- HISTORY
MODERN DRUG DISCOVERY
BIOINFORATICS IN DRUG DISCOVERY
DRUG DISCOVERY BASED ON BIOINFORMATIC TOOLS
BIOINFORMATICS IN COMPUTER-AIDED DRUG DISCOVERY
ECONOMICS OF DRUG DISCOVERY
CONCLUSION
REFERENCES
Putting the SPARK into Virtual Training.pptxCynthia Clay
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Personal Brand Statement:
As an Army veteran dedicated to lifelong learning, I bring a disciplined, strategic mindset to my pursuits. I am constantly expanding my knowledge to innovate and lead effectively. My journey is driven by a commitment to excellence, and to make a meaningful impact in the world.
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Cultivating and maintaining discipline within teams is a critical differentiator for successful organisations.
Forward-thinking leaders and business managers understand the impact that discipline has on organisational success. A disciplined workforce operates with clarity, focus, and a shared understanding of expectations, ultimately driving better results, optimising productivity, and facilitating seamless collaboration.
Although discipline is not a one-size-fits-all approach, it can help create a work environment that encourages personal growth and accountability rather than solely relying on punitive measures.
In this deck, you will learn the significance of workplace discipline for organisational success. You’ll also learn
• Four (4) workplace discipline methods you should consider
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• Three (3) key tips to maintain a disciplined workplace.
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[Note: This is a partial preview. To download this presentation, visit:
https://www.oeconsulting.com.sg/training-presentations]
Sustainability has become an increasingly critical topic as the world recognizes the need to protect our planet and its resources for future generations. Sustainability means meeting our current needs without compromising the ability of future generations to meet theirs. It involves long-term planning and consideration of the consequences of our actions. The goal is to create strategies that ensure the long-term viability of People, Planet, and Profit.
Leading companies such as Nike, Toyota, and Siemens are prioritizing sustainable innovation in their business models, setting an example for others to follow. In this Sustainability training presentation, you will learn key concepts, principles, and practices of sustainability applicable across industries. This training aims to create awareness and educate employees, senior executives, consultants, and other key stakeholders, including investors, policymakers, and supply chain partners, on the importance and implementation of sustainability.
LEARNING OBJECTIVES
1. Develop a comprehensive understanding of the fundamental principles and concepts that form the foundation of sustainability within corporate environments.
2. Explore the sustainability implementation model, focusing on effective measures and reporting strategies to track and communicate sustainability efforts.
3. Identify and define best practices and critical success factors essential for achieving sustainability goals within organizations.
CONTENTS
1. Introduction and Key Concepts of Sustainability
2. Principles and Practices of Sustainability
3. Measures and Reporting in Sustainability
4. Sustainability Implementation & Best Practices
To download the complete presentation, visit: https://www.oeconsulting.com.sg/training-presentations
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What might I learn?
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Who might benefit? Anyone and everyone leading folks from the shop floor to top floor.
Dr. William Harvey is a seasoned Operations Leader with extensive experience in chemical processing, manufacturing, and operations management. At Michelman, he currently oversees multiple sites, leading teams in strategic planning and coaching/practicing continuous improvement. William is set to start his eighth year of teaching at the University of Cincinnati where he teaches marketing, finance, and management. William holds various certifications in change management, quality, leadership, operational excellence, team building, and DiSC, among others.
Remote sensing and monitoring are changing the mining industry for the better. These are providing innovative solutions to long-standing challenges. Those related to exploration, extraction, and overall environmental management by mining technology companies Odisha. These technologies make use of satellite imaging, aerial photography and sensors to collect data that might be inaccessible or from hazardous locations. With the use of this technology, mining operations are becoming increasingly efficient. Let us gain more insight into the key aspects associated with remote sensing and monitoring when it comes to mining.
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2. Introduction
• In the past most drugs have been discovered either by
identifying the active ingredient from traditional
remedies or by serendipitous discovery.
• But now we know diseases are controlled at molecular
and physiological level.
• Also shape of an molecule at atomic level is well
understood.
• Information of Human Genome
3. History of Drug Discovery :
Pre 1919
• Herbal Drugs
• Serendiptious discoveries
1920s, 30s
• Vitamins
• Vaccines
1940s
• Antibiotic Era
• R&D Boost due to WW2
1950s
• New technology,
• Discovery of DNA
1960s
• Breakthrough in Etiology
1970s
• Rise of Biotechnology
• Use of IT
1980s
• Commercialization of
Drug Discovery
• Combinatorial Chemistry
1990s
• Robotics
• Automation
4. Registration:
• The Ministry of health & Family Welfare and the
Ministry of Chemicals & Fertilizers have major role in
regulation of IPM.
• NDA must be submitted to DCGI
• Phase III study reported to CDL, Kolkata
• Package inserted approved by DCI
• Marketing approval from FDA
5. • ~$800 M spent to bring a new drug to
market.
• $127 Billion spent on Pharma R&D in
2010
• Share of CROs in research operations
is 27%
• World CRO market is 16.3 B (Indian
share $500 M)
Market Scenerio:
18.8
R&D Share
6. Top CROs (By Revenue)
Contract Research Organizations Revenue
Quintiles $2.5 Billion
Pharmaceutical Product Development $1.8 Billion
Covance $1.4 Billion
Charles River Laboratories $1.2 Billion
Parexel $930 Million
Icon $887 Million
Kendle $590 Million
Pharmanet $470 Million
PRA International $410 Million
4G Pharmacovigilance $391 Million
7. Top CROs (India)
Contract Research Organizations Location
Actimus Biosciences Hyderabad
Advinus Therapeutics Bangalore
Aurigene Discovery technologies Bangalore
Chembiotek Kolkata
GVK Biosciences Hyderabad
Jubilant Organosys Bangalore
Ranbaxy Life Sciences Mumbai
Reliance Life Sciences Mumbai
Suven Life Sciences Hyderabad
Syngene Bangalore
8. Most valuable R&D Projects
Rank Product Company Phase Pharmacological class
Today's
NPV($mn)
1 Degludec Novo Nordisk Phase III Insulin 5,807
2 Tofacitinib Pfizer Phase III JAK-3 inhibitor 4,953
3 BG-12 Biogen Idec Phase III Fumarate 4,666
4 Incivek J & J Phase IV Hep C protease inhibitor 4,332
5 Relovair Theravance Phase III Corticosteroid 4,241
6 DR Cysteamine Undisclosed Phase III
Lysosomal transport
modulator
4,155
7 AMR 101 Undisclosed Phase III Omega-3 fatty acid 4,052
8 Eliquis Bristol Myers Squibb Phase IV Factor Xa inhibitor 3,836
9 Eliquis Pfizer Phase IV Factor Xa inhibitor 3,592
10 Bexssero Novartis Phase IV Meningococcal B vaccine 3,250
9. Top Companies by R&D Expense:
Sr. No. Company R & D spend($bn),2010
1 Novartis 7.9
2 Merck & Co 8.1
3 Roche 7.8
4 GlaxoSmithKline 5.7
5 Sanofi 5.8
6 Pfizer 9.1
7 Johnson & Johnson 4.5
8 Eli Lilly 4.7
9 AstraZeneca 4.2
10 Takeda 3.4
11 Bayer 2.3
12 Bristol-Myers Squibb 3.3
13 Boehringer Ingelheim 3.1
14 Amgen 2.8
15 Novo Nordisk 1.7
10. Drug Development Cost Break-up
R&D Function %
Discovery/Basic Research
Synthesis & Extraction 10.0
Biological Screening & testing 14.2
Preclinical Testing
Toxicology & Safety testing 4.5
Pharmaceutical Dosage Formulation 7.3
Clinical Trials
Phase I, II, III 29.1
Phase IV 11.7
Manufacturing & QC 8.3
IND & NDA 4.1
Bioavailability 1.8
Others 9.0
Total 100.0
11. 10,000
COMPOUNDS
250
COMPOUNDS 5 COMPOUNDS
1 FDA
APPROVED
DRUG
~6.5 YEARS ~7 YEARS ~1.5 YEARS
DRUG
DISCOVERY
PRECLINICAL
CLINICAL TRIALS FDA
REVIEW
Drug Discovery &
Development-Timeline
12. Drug Discovery
• Drugs Discovery methods:
– Random Screening
– Molecular Manipulation
– Molecular Designing
– Drug Metabolites
– Serendipity
13. Target
Selection
• Cellular and
Genetic
Targets
• Genomics
• Proteomics
• Bioinformatics
Lead
Discovery
• Synthesis and
Isolation
• Combinatorial
Chemistry
• Assay
development
• High-
Throughput
Screening
Medicinal
Chemistry
• Library
Development
• SAR Studies
• In Silico
Screening
• Chemical
Synthesis
In Vitro
Studies
• Drug Affinity
and
Selectivity
• Cell Disease
Models
• MOA
• Lead
Candidate
Refinement
In Vivo
Studies
• Animal
models of
Disease States
• Behavioural
Studies
• Functional
Imaging
• Ex-Vivo
Studies
Clinical
Trials and
Therapeutics
14. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
• Target selection in drug discovery is defined as the
decision to focus on finding an agent with a particular
biological action that is anticipated to have therapeutic
utility — is influenced by a complex balance of scientific,
medical and strategic considerations.
• Target identification: to identify molecular targets that
are involved in disease progression.
• Target validation: to prove that manipulating the
molecular target can provide therapeutic benefit for
patients.
15. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Biochemical Classes of Drug Targets
G-protein coupled receptors - 45%
enzymes - 28%
hormones and factors - 11%
ion channels - 5%
nuclear receptors - 2%
Techniques for Target Identification
16. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Cellular & Genetic Targets:
Involves the identification of the function of a potential therapeutic drug
target and its role in the disease process.
For small-molecule drugs, this step in the process involves identification
of the target receptors or enzymes whereas for some biologic
approaches the focus is at the gene or transcription level.
Drugs usually act on either cellular or genetic chemicals in the body,
known as targets, which are believed to be associated with disease.
17. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Cellular & Genetic Targets:
Scientists use a variety of techniques to identify and
isolate individual targets to learn more about their
functions and how they influence disease.
Compounds are then identified that have various
interactions with the drug targets that might be
helpful in treatment of a specific disease.
18. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Genomics:
The study of genes and their function. Genomics aims to
understand the structure of the genome, including the mapping
genes and sequencing the DNA.
Seeks to exploit the findings from the sequencing of the human
and other genomes to find new drug targets.
Human Genome consists of a sequence of around 3 billion
nucleotides (the A C G T bases) which in turn probably encode
35,000 – 50,000 genes.
19. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Genomics:
Drew’s estimates that the number of genes implicated in disease,
both those due to defects in single genes and those arising from
combinations of genes, is about 1,000
Based on 5 or 10 linked proteins per gene, he proposes that the
number of potential drug targets may lie between 5,000 and
10,000.
Single Nucleotide Polymorphism (SNP) libraries: are used to
compare the genomes from both healthy and sick people and to
identify where their genomes vary.
20. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Proteomics:
It is the study of the proteome, the complete set of proteins
produced by a species, using the technologies of large – scale protein
separation and identification.
It is becoming increasingly evident that the complexity of biological
systems lies at the level of the proteins, and that genomics alone will
not suffice to understand these systems.
It is also at the protein level that disease processes become manifest,
and at which most (91%) drugs act.
Therefore, the analysis of proteins (including protein-protein, protein-
nucleic acid, and protein ligand interactions) will be utmost importance
to target discovery.
21. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Proteomics:
Proteomics is the systematic high-throughput separation
and characterization of proteins within biological systems.
Target identification with proteomics is performed by
comparing the protein expression levels in normal and
diseased tissues.
2D PAGE is used to separate the proteins, which are
subsequently identified and fully characterized with LC-
MS/MS.
22. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Bioinformatics:
Bioinformatics is a branch of molecular biology that involves extensive analysis of
biological data using computers, for the purpose of enhancing biological research.
It plays a key role in various stages of the drug discovery process including
target identification
computer screening of chemical compounds and
pharmacogenomics
23. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Bioinformatics:
Bioinformatics methods are used to transform the raw sequence
into meaningful information (eg. genes and their encoded
proteins) and to compare whole genomes (disease vs. not).
Can compare the entire genome of pathogenic and non-
pathogenic strains of a microbe and identify genes/proteins
associated with pathogenism
Using gene expression micro arrays and gene chip technologies, a
single device can be used to evaluate and compare the
expression of up to 20000 genes of healthy and diseased
individuals at once
24. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Synthesis and
Isolation
Combinatorial
Chemistry
Assay
Development
High
Throughput
Screening
Lead Discovery:
• Identification of small molecule modulators of
protein function
• The process of transforming these into high-
content lead series.
25. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Synthesis and
Isolation
Combinatorial
Chemistry
Assay
Development
High
Throughput
Screening
Synthesis and Isolation:
• Separation of mixture
• Separation of impurities
• In vitro chemical synthesis
• Biosynthetic intermediate
26. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Synthesis and
Isolation
Combinatorial
Chemistry
Assay
Development
High
Throughput
Screening
Combinatorial Chemistry:
Rapid synthesis of or computer simulation of
large no. of different but structurally related
molecules
• Search new leads
• Optimization of target affinity & selectivity.
• ADME properties
• Reduce toxicity and eliminate side effects
27. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Synthesis and
Isolation
Combinatorial
Chemistry
Assay
Development
High
Throughput
Screening
Assay Development
• Used for measuring the activity of a drug.
• Discriminate between compounds.
• Evaluate:
• Expressed protein targets.
• Enzyme/ substrate interactions.
28. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Synthesis and
Isolation
Combinatorial
Chemistry
Assay
Development
High
Throughput
Screening
High throughput screening:
• Screening of drug target against selection of
chemicals.
• Identification of highly target specific
compounds.
29. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Synthesis and
Isolation
Combinatorial
Chemistry
Assay
Development
High
Throughput
Screening
High throughput screening:
30. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Library
Development
SAR Studies
In Silico
Screening
Chemical
Synthesis
Medicinal Chemistry:
• It’s a discipline at the intersection of synthetic
organic chemistry and parmacology.
• Focuses on small organic molecules (and not
on biologics and inorganic compounds)
• Used in
• Drug discovery (hits)
• Lead optimization (hit to lead)
• Process chemistry and development
31. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Library
Development
SAR Studies
In Silico
Screening
Chemical
Synthesis
Library Development:
• Collection of stored chemicals along with
associated database.
• Assists in High Throughput Screening
• Helps in screening of drug target (hit)
• Based on organic chemistry
32. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Library
Development
SAR Studies
In Silico
Screening
Chemical
Synthesis
SAR Studies:
• Helps identify pharmacophore
• The pharmacophore is the precise section of
the molecule that is responsible for biological
activity
• Enables to prepare more active compound
• Allow elimination of excessive functionality
34. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Library
Development
SAR Studies
In Silico
Screening
Chemical
Synthesis
In silico screening:
• Computer simulated screening of chemicals
• Helps in finding structures that are most likely
to bind to drug target.
• Filter enormous Chemical space
• Economic than HTS
35. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Library
Development
SAR Studies
In Silico
Screening
Chemical
Synthesis
Chemical Synthesis:
• Involve production of lead compound in
suitable quantity and quality to allow large
scale animal and eventual, extensive human
clinical trials
• Optimization of chemical route for bulk
industrial production.
• Suitable drug formulation
36. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Drug Affinity
and Selectivity
Cell Disease
Models
MOA
Lead Candidate
Refinement
In Vitro Studies:
• (In glass) studies using component of organism i.e. test tube
experiments
• Examples-
• Cells derived from multicellular organisms
• Subcellular components (Ribosomes, mitochondria)
• Cellular/ subcellular extracts (wheat germ, reticulocyte
extract)
• Purified molecules (DNA,RNA)
37. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Drug Affinity
and Selectivity
Cell Disease
Models
MOA
Lead Candidate
Refinement
In Vitro Studies:
Advantages:
• Studies can be completed in short period of time.
• Reduces risk in post clinical trials
• permits an enormous level of simplification of the system
• investigator can focus on a small number of components
38. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Drug Affinity
and Selectivity
Cell Disease
Models
MOA
Lead Candidate
Refinement
Drug affinity and selectivity
• Drug affinity is the ability of drug to bind to its biological
target (receptor, enzyme, transport system, etc.)
• Selectivity- Drug should bind to specific receptor site on the
cell (eg. Aspirin)
39. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Drug Affinity
and Selectivity
Cell Disease
Models
MOA
Lead Candidate
Refinement
• Isogenic human disease models- are a family of cells that are
selected or engineered to accurately model the genetics of a specific
patient population, in vitro
• Stem cell disease models-Adult or embryonic stem cells carrying
or induced to carry defective genes can be investigated in vitro to
understand latent molecular mechanisms and disease characteristics
Cell disease models
40. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Drug Affinity
and Selectivity
Cell Disease
Models
MOA
Lead Candidate
Refinement
• Optimizing chemical hits for clinical trial is commonly referred
to as lead optimization
• The refinement in structure is necessary in order to improve
• Potency
• Oral Availability
• Selectivity
• pharmacokinetic properties
• safety (ADME properties)
Lead Candidate refinement
41. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Animal models of
Disease States
Behavioural
Studies
Functional
Imaging
Ex-Vivo Studies
In vivo studies
• Its experimentation using a whole, living
organism.
• Gives information about,
• Metabolic profile
• Toxicology
• Drug interaction
42. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Animal models of
Disease States
Behavioural
Studies
Functional
Imaging
Ex-Vivo Studies
Animal models of disease states
• Test conditions involving induced disease or
injury similar to human conditions.
• Must be equivalent in mechanism of cause.
• Can predict human toxicity in 71% of the
cases.
• Eg. SCID mice-HIV
NOD mice- Diabetes
Danio rerio- Gene function
43. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Animal models of
Disease States
Behavioural
Studies
Functional
Imaging
Ex-Vivo Studies
Behavioural Studies
• Tools to investigate behavioural results of drugs.
• Used to observe depression and mental disorders.
• However self esteem and suicidality are hard to induce.
• Example:
• Despair based- Forced swimming/ Tail suspension
• Reward based
• Anxiety Based
44. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Animal models of
Disease States
Behavioural
Studies
Functional
Imaging
Ex-Vivo Studies
Functional Imaging:
• Method of detecting or measuring changes in
metabolism, blood flow, regional chemical
composition, and absorption.
• Tracers or probes used.
• Modalities Used-
• MRI
• CT-Scan
45. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Animal models of
Disease States
Behavioural
Studies
Functional
Imaging
Ex-Vivo Studies
Ex-Vivo Studies:
• Experimentation on tissue in an artificial
environment outside the organism with the
minimum alteration of natural conditions.
• Counters ethical issues.
• Examples:
• Measurement of tissue properties
• Realistic models for surgery
46. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Clinical trials:
• Set of procedures in medical research and
drug development to study the safety and
efficacy of new drug.
• Essential to get marketing approval from
regulatory authorities.
• May require upto 7 years.
47. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase 0:
• Recent designation, also known as human micro-dosing
studies.
• First in human trials, conducted to study exploratory
investigational new drug.
• Designed to to speed up the development of promising
drugs.
• Concerned with-
• Preliminary data on the drug’s pharmacodynamics
and pharmacokinetics
• Efficacy of pre-clinical studies.
48. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase I:
• Clinical Pharmacologic Evaluation
• First stage of testing in human subjects.
• 20-50 Healthy Volunteers
• Concerned With:
– Human Toxicity.
– Tolerated Dosage Range
– Pharma-cology/dynamics
49. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase I:
Types of Phase-I Trials
• SAD (Single Ascending Dose)
• MAD (Multiple Ascending Dose)
• Food effect
50. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase II:
• Controlled Clinical Evaluation.
• 50-300 Patients
• Controlled Single Blind Technique
• Concerned With:
– Safety
– Efficacy
– Drug Toxicity
– Drug Interaction
51. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase III:
• Extended Clinical Trials.
• Most expensive & time consuming.
• 250-1000 Patients.
• Controlled Double Blind Technique.
• Concerned With:
– Safety, Efficacy
– Comparison with other Drugs
– Package Insert
52. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase IV:
• Post Marketing Surveillance.
• Designed to detect any rare or long-term
adverse effects.
• Adverse Drug Reaction Monitoring.
• Pharmacovigilance.
53. 10,000
COMPOUNDS
250
COMPOUNDS 5 COMPOUNDS
1 FDA
APPROVED
DRUG
~6.5 YEARS ~7 YEARS ~1.5 YEARS
DRUG
DISCOVERY
PRECLINICAL
CLINICAL TRIALS FDA
REVIEW
Drug Discovery &
Development-Timeline
54. Gene Therapy
• Technique for correcting
defective genes.
• It is the process of inserting
genes into cells to treat
diseases.
• Gene therapy is used to
correct a deficient phenotype.
55. Gene Therapy-Approaches
Germline Gene Therapy
Sperm or eggs, are modified by the introduction of functional genes, which
are integrated into their genomes.
Change would be heritable and would be passed on to later generations.
Somatic Gene Therapy
The therapeutic genes are transferred
Into the somatic cells of a patient.
Change will not be inherited by the
patient's offspring or later generations.
56. Gene Therapy- Types
Ex Vivo Gene Therapy
Transfer of therapeutic genes in cultured cells which are then reintroduced
into patient.
Eg: Therapy for ADA Deficiency
In Vivo Gene Therapy
The direct delivery of genes into the cells of a particular tissue is referred
to as in vivo gene therapy.
Eg: Therapy for Cystic fibrosis
57. Gene Therapy- Vectors
• Viruses
Retroviruses
Adenoviruses
Adeno-associated viruses
Herpes Simplex viruses
• Pure DNA Constructs
• Lipoplexes
• DNA Molecular Conjugates
• Human Artificial Chromosome
58. Gene Therapy- Limitations
• Short lived nature of gene therapy
• Immune response
• Problems with viral vectors
• Multigene disorders
59. Recent Developments
• Nanotechnology + gene therapy yielded treatment to
torpedo cancer
• Results of world's first gene therapy for inherited
blindness show sight improvement
• New Method of Gene Therapy Alters Immune Cells for
Treatment of Advanced Melanoma
• Dual Gene Therapy Suppresses Lung Cancer in
Preclinical Test
60. Orphan Drugs:
• An orphan drug is a pharmaceutical agent that has been
developed specifically to treat a rare medical condition,
the condition itself being referred to as an orphan disease.
• National Organization for Rare
Disorders
• European Organization for Rare
Diseases
61. Advantages:
• Tax incentives.
• Enhanced patent protection and marketing rights.
• Clinical research financial subsidization.
• Rise in research and developmen.
• Crown Corporation.
62. Orphan Drugs Act:
• 4th January 1983
• 6000 Orphan Diseases
• Unprofitable Drug Development
• Affecting < 2,00,000 Persons
• Orphan Drug Status to 1,090
Drugs
• 1985 Amendment- Marketing
Exclusivity
Tourette Syndrome
An Orphan Disease
63. FDA Orphan Drug Approvals:
43
19
17
19
2
% Share
Big Pharma
Small Biopharma
Established
Biopharma
Small & Medium
Pharma