The document provides an overview of the drug discovery process. It discusses the various stages involved including target selection, lead discovery, medicinal chemistry, in vitro studies, in vivo studies, and clinical trials.
Target selection involves identifying biological targets implicated in disease through methods like genomics, proteomics, and bioinformatics. Lead discovery focuses on identifying small molecule modulators through synthesis, combinatorial chemistry, assay development, and high-throughput screening. Medicinal chemistry optimizes leads through approaches such as library development, SAR studies, in silico screening, and chemical synthesis. In vitro and in vivo studies evaluate drug candidates prior to clinical trials in humans.
Target identification, target validation, lead identification and lead
Optimization.
• Economics of drug discovery.
• Target Discovery and validation-Role of Genomics, Proteomics and
Bioinformatics.
• Role of Nucleic acid microarrays, Protein microarrays, Antisense
technologies, siRNAs, antisense oligonucleotides, Zinc finger proteins.
• Role of transgenic animals in target validation.
Target identification, target validation, lead identification and lead
Optimization.
• Economics of drug discovery.
• Target Discovery and validation-Role of Genomics, Proteomics and
Bioinformatics.
• Role of Nucleic acid microarrays, Protein microarrays, Antisense
technologies, siRNAs, antisense oligonucleotides, Zinc finger proteins.
• Role of transgenic animals in target validation.
molecular docking its types and de novo drug design and application and softw...GAUTAM KHUNE
This ppt deals with all the aspects related to molecular docking ,its types(rigid ,flexible and manual) and screening based on it and also deals with de novo drug design , various softwares available for docking methodologies and applications for molecular docking in new drug design
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.
Role of Target Identification and Target Validation in Drug Discovery ProcessPallavi Duggal
Target identification and Validation tells about the how target is neccesary for new drug discovery and its development to reach into market for rare diseases.
This presentation provides a knowledge about Safety Pharmacology, It's aim & objectives, issues, consideration in selection and design of study and test study, duration of study, various studies involved in safety pharmacology, its guidelines, preclinical safety pharmacology. An assignment for the subject, Clinical Research and Pharmacovigilance, 1st year M.Pharm, 2nd semester.
Target Validation
Introduction,Drug discovery, Target identification and validation, Target validation and techniques
By
Ms. B. Mary Vishali
Department of Pharmacology
Drug discovery and development is and always has been the most exciting part of clinical pharmacology. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
molecular docking its types and de novo drug design and application and softw...GAUTAM KHUNE
This ppt deals with all the aspects related to molecular docking ,its types(rigid ,flexible and manual) and screening based on it and also deals with de novo drug design , various softwares available for docking methodologies and applications for molecular docking in new drug design
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.
Role of Target Identification and Target Validation in Drug Discovery ProcessPallavi Duggal
Target identification and Validation tells about the how target is neccesary for new drug discovery and its development to reach into market for rare diseases.
This presentation provides a knowledge about Safety Pharmacology, It's aim & objectives, issues, consideration in selection and design of study and test study, duration of study, various studies involved in safety pharmacology, its guidelines, preclinical safety pharmacology. An assignment for the subject, Clinical Research and Pharmacovigilance, 1st year M.Pharm, 2nd semester.
Target Validation
Introduction,Drug discovery, Target identification and validation, Target validation and techniques
By
Ms. B. Mary Vishali
Department of Pharmacology
Drug discovery and development is and always has been the most exciting part of clinical pharmacology. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
A presentation outlining the various processes a chemical compound undergoes (thorough & rigorous screening procedures) before it is finally introduced into the drug market
Dialogue with Canada’s leading regulatory and assessment experts: Health Canada Bureau of Biologics and Genetic Therapies (BGTD) and Canadian Agency for Drugs and Technologies in Health (CADTH)
Date: June 29, 2016
Time: 1:00pm to 3:00pm EST
Saudi Commission for Health Specialties, Part 1 of the series of lectures I gave for the PEER (Professionalism and Ethics Education for Residents) Project sponsored and organized by the Saudi Commission for Health Specialties (SCHS).
2016-11-28 Mentlife seminar: Pharmaceutical Drug Development; An Overall Pers...MentLife
This seminar provided an understanding of modern pharmaceutical drug development – the different phases of drug development and insight into different jobs.
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.
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
4th International Conference on Biomarkers & Clinical Research, will be organized around the theme "Impact of Biomarker Developments in Health Diagnostics and Clinical Research."
Drugs Discovery and Development from Microbial Genome.pptxLunjapikai Haokip
Microbes have made a phenomenal contribution to the health and well-being of people throughout the world. In addition to producing many primary metabolites, such as amino acids, vitamins and nucleotides, they are capable of making secondary metabolites, which constitute half of the pharmaceuticals on the market today and provide agriculture with many essential products. This review centers on these beneficial secondary metabolites, the discovery of which goes back 80 years to the time when penicillin was discovered by Alexander Fleming.
Personalized medicine involves the prescription of specific therapeutics best suited for an individual based on their genetic or proteomic profile. This talk discusses current approaches in drug discovery/development, the role of genetics in drug metabolism, and lawful/ethical issues surrounding the deployment of new health technology.
Respiratory stimulants: types, complete discussion on indications, contraindications, assessment, patient notes and examples of stimulants both central and respiratory
Expectorants and Antitussives: types, complete discussion on indications, contraindications, assessment, patient notes and examples of expectorants and antitussives
Complete pharmacology of Non steroidal Anti inflammatory Drugs, classification, Mechanism of action, Pharmacological actions, Indications, Contraindications, Adverse effects
Pharmacology laboratory experiment, both invivo and invitro includes interpolation, matching , bracketing, three point, four point bioassays with a note on hypoglycemic activity, acute skin irritation, acute eye irritaiton, pyrogen test, gastrointestinal motility test, physiological salt solutions
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
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Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
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.
$182 Billion spent on Pharma R&D in 2016
Share of CROs in research operations is 27%
World CRO market is 16.3 B (Indian share $500 M)
Market Scenerio:
6. Top CROs (By Revenue)
Contract Research Organizations Firm focus on
Quintiles Clinical development to marketing
Covance Clinical research
Parexel Biopharma, medical devices, diagnostics
InVentiv Health Clinical development to marketing
Icon Genomic sciences and oncology
PRA Health Sciences Biologics and bioanalytics
PPD Drug development process
Charles River Laboratories Pharmaceutical and agricultures services
Chiltern Clinical data managment
INC research Late stage clinical trials
7. Top CROs (India)
Contract Research Organizations Location
Actimus Biosciences Hyderabad
Advinus Therapeutics Bangalore
Aurigene Discovery technologies Bangalore
Chembiotek Kolkata
GVK Biosciences Hyderabad
Jubilant Organosys Bangalore
Ranbaxy Life Sciences Mumbai
Reliance Life Sciences Mumbai
Suven Life Sciences Hyderabad
Syngene Bangalore
8. Most valuable R&D Projects
Rank Product Company Phase Pharmacological class
Today's
NPV($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
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
The decision to focus on finding an agent with a particular biological
action that is anticipated to have therapeutic utility.
Target identification: 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
Where as 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
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.
18. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Cellular &
Genetic Targets
Genomics
Proteomics
Bioinformatics
Genomics:
Drew’s et al 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
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.
19. 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 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.
20. 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.
21. 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
Pharmacogenomics
22. 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
Can compare the entire genome of pathogenic and non-
pathogenic strains of a microbe
Using gene expression micro arrays and gene chip
technologies,
single device can be used to evaluate and compare the
expression of up to 20000 genes of healthy and diseased
individuals at once
23. 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.
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
Synthesis and Isolation:
Separation of mixture
Separation of impurities
In vitro chemical synthesis
Biosynthetic intermediate
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
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
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
Assay Development
• Used for measuring the activity of a drug.
• Discriminate between compounds.
• Evaluate:
• Expressed protein targets.
• Enzyme/ substrate interactions.
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
High throughput screening:
Screening of drug target against selection of
chemicals.
Identification of highly target specific
compounds.
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:
29. 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 pharmacology.
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
30. 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
31. 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
33. 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
34. 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
35. 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 (simulated experiments)
Examples-
• Cells derived from multicellular organisms
• Subcellular components (Ribosomes, mitochondria)
• Cellular/ subcellular extracts (wheat germ, reticulocyte
extract)
• Purified molecules (DNA,RNA)
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:
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
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
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)
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
• 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
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
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
40. 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
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
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
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
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
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
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
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
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
45. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Clinical trials:
An investigational new drug application (IND) : outlines what the
sponsor of a new drug proposes for human testing in clinical trials.
Phase 0
Phase I studies
Phase II studies
Phase III studies
Submission of New Drug Application (NDA) is the formal step asking
the FDA to consider a drug for marketing approval.
FDA reviewers will approve the application or find it either
"approvable" or "not approvable."
Phase IV studies
49. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase 0:
Study of new drug in microdoses to derive PK information in human
before undertaking phase I studies is called PHASE O
Microdose: Less than 1/100 of the dose of a test substance calculated
to produce pharmacological effect with a max dose ≤100 micrograms
Objective: To obtain preliminary Pharmacokinetic data.
Preclinical Data: Subacute toxicity study in one species by two routes
of administration.
50. 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 and Tolerated Dosage Range
– Pharmacokinetics
– Pharmacology/dynamics
51. 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
52. 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
53. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase II Types:
Phase IIA: Designed to assess dosing requirements
Phases IIB: Designed to study efficacy
Phase IIA Phase IIB
EARLY PHASE LATE PHASE
Pilot clinical trials Pivotal clinical trials
20-200 PATIENTS 50-300 PATIENTS
Not multicentric Multicentric
SINGLE BLIND comparison with a
standard drug
DOUBLE BLIND compared with a
placebo or standard drug
54. 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
55. Target Selection Lead
Discovery
Medicinal
Chemistry
In Vitro
Studies
In Vivo
Studies
Clinical
Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase IIIa Phase IIIb
Prior to NDA After the NDA but prior to the
approval and launch.
Generates data on safety and efficacy These may supplement or complete the
earlier trials or may be directed to
Phase IV trials
Phase III Studies : End of Clinical Trial Activities
Sponsor: Expert Committee review of Efficacy, safety and potential
sales (Profit).
Go-No Go decision to file new drug application with DCGI
Expert review by DCGI’s Committee
DCGI approval
NCE marketed :Phase IV begins
56. 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.
57. 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
58. 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.
59. Gene Therapy-Approaches
Germ line 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.
60. Gene Therapy- Types
Ex Vivo Gene Therapy
Transfer of therapeutic genes in cultured cells which
are then reintroduced into patient.
In Vivo Gene Therapy
The direct delivery of genes into the cells of a
particular tissue is referred to as in vivo gene therapy.
61. Gene Therapy- Vectors
• Viruses
Retroviruses
Adenoviruses
Adeno-associated viruses
Herpes Simplex viruses
• Pure DNA Constructs
• Lipoplexes
• DNA Molecular Conjugates
• Human Artificial Chromosome
62. 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