The document discusses the process of drug discovery, including target selection, lead discovery, medicinal chemistry, in vitro and in vivo studies, 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, assay development, and high-throughput screening. Medicinal chemistry then works to optimize these leads. [/SUMMARY]
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
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
Target Validation
Introduction,Drug discovery, Target identification and validation, Target validation and techniques
By
Ms. B. Mary Vishali
Department of Pharmacology
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.
Requirements And Guidelines For Permission To Import / or Manufacture of New Drugs For Sale or To Undertake Clinical Trials
Schedule Y was introduced under the Drugs and Cosmetics Act 1940, to
introduce requirements for countries to get permission for:
Importing
Manufacturing new drugs
Conducting Clinical Trials.
Application for permission
Clinical Trial
Studies in specific population
Post marketing surveillance
Special studies: BA/BE studies
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
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.
Introduction to pre clinical screening of drugsKanthlal SK
Various Techniques and Methods for screening of new chemical entities in preclinical aspects (both invitro & invivo) for effective and safe clinical usage.
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 Validation
Introduction,Drug discovery, Target identification and validation, Target validation and techniques
By
Ms. B. Mary Vishali
Department of Pharmacology
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.
Requirements And Guidelines For Permission To Import / or Manufacture of New Drugs For Sale or To Undertake Clinical Trials
Schedule Y was introduced under the Drugs and Cosmetics Act 1940, to
introduce requirements for countries to get permission for:
Importing
Manufacturing new drugs
Conducting Clinical Trials.
Application for permission
Clinical Trial
Studies in specific population
Post marketing surveillance
Special studies: BA/BE studies
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
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.
Introduction to pre clinical screening of drugsKanthlal SK
Various Techniques and Methods for screening of new chemical entities in preclinical aspects (both invitro & invivo) for effective and safe clinical usage.
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.
Drug Development Life Cycle - Costs and RevenueRobert Sturm
Presentation explains the Drug Development Process in terms of time/costs from initial research to final manufacturing. It presents strategies for increasing profits/decreasing costs, shows the impact of generics and details how Information Technology fits into this equation. It uses research from DiMasi and Grabowski to identify drug costs and product revenue.
Thyroid Hormone Disorders lecture :-
-Thyroid gland & Thyroid hormones.
-How does Thyroid hormone is formed ?
-Regulation of secretion.
-Hypothyroidism.
-Treatment of hypothyroidism .
-Administration of Levothyroxin.
-Levothyroxin interactions.
-Levothyroxin cautions.
-Hyperthyroidism .
-Symptoms & treatment of Hyperthyroidism.
-Removal of part or all of the thyroid.
-Blockade of hormone release .
-Inhibition of thyroid hormone synthesis.
-Mechanism of action of antithyroid.
-Administration of antithyroid drugs.
-Antithyroid drugs interactions.
-Antithyroid drugs cautions.
-General notes.
-Practical notes on levothyroxin.
-Practical notes on antithroid drugs.
-Rapid review.
-Test yourself.
4th International Conference on Biomarkers & Clinical Research, will be organized around the theme "Impact of Biomarker Developments in Health Diagnostics and Clinical Research."
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
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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!
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
- 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
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.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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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