1. Drug Discovery & Development

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. Drug Discovery & Development-Timeline
PRECLINICAL
CLINICAL TRIALS
FDA
REVIEW
10,000
COMPOUNDS
250
COMPOUNDS
1 FDA APPROVED DRUG
5 COMPOUNDS
~6.5 YEARS
~7 YEARS
~1.5 YEARS

5. Drug Discovery Drugs Discovery methods: Random Screening
Molecular Manipulation
Molecular Designing
Drug Metabolites
Serendipity

6. Clinical Trials and Therapeutics
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

7. Cellular & Genetic Targets
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.
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

8. Cellular & Genetic Targets
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
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

9. 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.
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

10. 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.
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

11. Cellular & Genetic Targets
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.
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

12. Cellular & Genetic Targets
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.
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

13. Cellular & Genetic Targets
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.
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

14. Cellular & Genetic Targets
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.
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

15. Cellular & Genetic Targets
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
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

16. Cellular & Genetic Targets
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 genes of healthy and diseased individuals at once
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

17. Lead Discovery:
Identification of small molecule modulators of protein function
The process of transforming these into high-content lead series.
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

18. Synthesis and Isolation:
Separation of mixture
Separation of impurities
In vitro chemical synthesis
Biosynthetic intermediate
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

19. 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
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

20. Assay Development Used for measuring the activity of a drug.
Discriminate between compounds.
Evaluate:
Expressed protein targets.
Enzyme/ substrate interactions.
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

21. High throughput screening:
Screening of drug target against selection of chemicals.
Identification of highly target specific compounds.
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

22. High throughput screening:
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

23. 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
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

24. 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
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

25. 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
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

26. SAR Studies: Morphine Molecule Library Development SAR Studies
In Silico Screening
Chemical Synthesis
Morphine Molecule
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

27. 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
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

28. 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
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

29. 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)
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

30. 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
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

31. 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)
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

32. Cell disease models
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
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

33. 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)
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

34. Animal models of Disease States
In vivo studies
Its experimentation using a whole, living organism.
Gives information about,
Metabolic profile
Toxicology
Drug interaction
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

35. 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
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

36. Animal models of Disease States
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
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

37. Animal models of Disease States
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
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

38. Animal models of Disease States
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
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

39. 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.
Phase-I
Phase-II
Phase-III
Phase-IV
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

40. 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.
Phase-I
Phase-II
Phase-III
Phase-IV
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

41. 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
Phase-I
Phase-II
Phase-III
Phase-IV
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

42. Phase I: Types of Phase-I Trials SAD (Single Ascending Dose)
MAD (Multiple Ascending Dose)
Food effect
Phase-I
Phase-II
Phase-III
Phase-IV
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

43. Phase II: Controlled Clinical Evaluation. 50-300 Patients
Controlled Single Blind Technique
Concerned With:
Safety
Efficacy
Drug Toxicity
Drug Interaction
Phase-I
Phase-II
Phase-III
Phase-IV
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

44. Phase III: Extended Clinical Trials. Most expensive & time consuming.
Patients.
Controlled Double Blind Technique.
Concerned With:
Safety, Efficacy
Comparison with other Drugs
Package Insert
Phase-I
Phase-II
Phase-III
Phase-IV
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

45. Phase IV: Post Marketing Surveillance.
Designed to detect any rare or long-term adverse effects.
Adverse Drug Reaction Monitoring.
Pharmacovigilance.
Phase-I
Phase-II
Phase-III
Phase-IV
Target Selection
Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials

46. Drug Discovery & Development-Timeline
PRECLINICAL
CLINICAL TRIALS
FDA
REVIEW
10,000
COMPOUNDS
250
COMPOUNDS
1 FDA APPROVED DRUG
5 COMPOUNDS
~6.5 YEARS
~7 YEARS
~1.5 YEARS