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.
HISTORY OF DRUG DISCOVERY
Pre 1919 1970s 1980s
• Herbal Drugs • Rise of Biotechnology • Commercialization of
• Serendiptious • Use of IT Drug Discovery
discoveries • Combinatorial Chemistry

1920s, 30s 1960s 1990s

• Vitamins • Breakthrough in Etiology • Robotics
• Vaccines • Automation

1940s 1950s
• Antibiotic Era • New technology,
• R&D Boost due to WW2 • Discovery of DNA
TOP COMPANIES BY R&D EXPENSE
Sr. No. Company R & D spend($bn)
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
THE PROCESS
THE PROCESS
In broader sense drug discovery and development can be defined
• “A process that starts with the identification of disease and therapeutic
target of interest and include methodology, assay development ,lead
identification and characterization in vitro ,formulation and animal
pharmacological studies ,pharmacokinetics and safety studies in animals
and clinical studies in the human .”Different stages include
 Basic research
 Feasibility studies
 Programme
 Non-Clinical development
 Clinical Development
 DRUG Drug Discovery &
DISCOVERY
Development-Timeline
PRECLINICAL

CLINICAL TRIALS FDA

10,000 250 REVIEW 1 FDA
COMPOUNDS COMPOUNDS 5 COMPOUNDS APPROVED
DRUG

~6.5 YEARS ~7 YEARS ~1.5 YEARS

 Target Lead Lead In Vitro Preclinical Clinical
Selection Discovery optimization Studies studies Trials and
Medicinal Therapeutics
• Cellular and • Synthesis and • chemistry
Library • Drug Affinity • Animal
Genetic Isolation Development and models of
Targets Selectivity Disease States

• Genomics • Combinatorial • SAR Studies • Cell Disease • Behavioural

Chemistry Models Studies

• Proteomics • Assay • In Silico • MOA • Functional

development Screening Imaging

• Bioinformatics • High- • Chemical • Lead • Ex-Vivo

Throughput Synthesis Candidate Studies
Screening Refinement
DRUG DISCOVERY
• It is phase during which the candidates or target of interest are selected on
the basis of their pharmacological bases
• Drugs Discovery methods:
– Random Screening
– Molecular Designing
– Drug Metabolites
– Serendipity
 TARGET SELECTION

• Target selection in drug discovery is defined as the decision to focus

Cellular &
Genetic Targets
on finding an agent with a particular biological action that is
anticipated to have therapeutic utility
Genomics
• Target identification: to identify molecular targets that are involved in
disease progression.
Proteomics
• Target validation: to prove that manipulating the molecular target can
Bioinformatics provide therapeutic benefit for patients.

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 TARGET SELECTION
Biochemical Classes of Drug Targets
 G-protein coupled receptors - 45%
Cellular &
Genetic Targets  enzymes - 28%
 hormones and factors - 11%
Genomics  ion channels - 5%
 nuclear receptors - 2%
Proteomics
Techniques for Target Identification
Bioinformatics

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Cellular & Genetic Targets

•Involves the identification of the function of a

Cellular &
Genetic Targets
potential therapeutic drug target and its role in
the disease process
Genomics

Proteomics •Drugs usually act on either cellular or genetic

chemicals in the body, known as targets, which
Bioinformatics are believed to be associated with disease.
Target Selection Lead Medicinal In Vitro Preclinical Clinical
Discovery Chemistry Studies studies Trials
  Genomics
•The study of genes and their function. Genomics
Cellular & aims to understand the structure of the genome,
Genetic Targets including the mapping genes and sequencing the
DNA.
Genomics

Proteomics
•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.
Bioinformatics

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Proteomics
•It is the study of the proteome, the complete set of proteins
produced by a species, using the technologies of large –
Cellular &
scale protein separation and identification.
Genetic Targets

•It is also at the protein level that disease processes become

Genomics manifest, and at which most (91%) drugs act.
•Therefore, the analysis of proteins (including protein-protein,
Proteomics
protein-nucleic acid, and protein ligand interactions) will be
utmost importance to target discovery.
Bioinformatics

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Continued….
•Proteomics is the systematic high-throughput
Cellular &
separation and characterization of proteins
Genetic Targets within biological systems.
Genomics
•Target identification with proteomics is
Proteomics
performed by comparing the protein
expression levels in normal and diseased
Bioinformatics tissues.
Target Selection Lead Medicinal In Vitro Preclinical Clinical
Discovery Chemistry Studies studies Trials
 Bioinformatics
Bioinformatics is a branch of molecular biology that involves extensive
Cellular &
Genetic Targets analysis of biological data using computers, for the purpose of enhancing
biological research.
Genomics It plays a key role in various stages of the drug discovery process including
 target identification
Proteomics  computer screening of chemical compounds and

Bioinformatics

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Continued…
•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).
Cellular &
Genetic Targets
•Can compare the entire genome of pathogenic and non-
pathogenic strains of a microbe and identify genes/proteins
Genomics associated with pathogenism
•Using gene expression micro arrays and gene chip technologies, a
Proteomics single device can be used to evaluate and compare the expression
of up to 20000 genes of healthy and diseased individuals at once

Bioinformatics

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 LEAD DISCOVERY
• A lead compound is an organic molecule that act as
a prototype drug around which further optimization
Synthesis and
Isolation is centered and focused”
Combinatorial
• Identification of small molecule modulators of
Chemistry protein function
Assay • The process of transforming these into high-content
Development
lead series.
High
Throughput
Screening

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Synthesis and Isolation
• Separation of mixture
Synthesis and
Isolation • Separation of impurities
Combinatorial • In vitro chemical synthesis
Chemistry
• Biosynthetic intermediate
Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
Approaches For Lead Discovery
Serendipity:

• It is to follow when chance is very less. It has been the historically the most successful way of
discovering the drugs. E.g discovery of lavemisol,Vaproic acid.

Endogenous Source:

• Human disease arises from disturbance of the normal biochemical processes. A logical
therapeutic approach is the administration of one or more of these naturally occurring
endogenous molecules or their analougues.The most important approach under this source is
Peptidomimetic Chemistry using non-peptides to mimic endogenous peptide activity.

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
Continued…
Exogenous Source: (Ethanobotany or Ethanopharmacology)

• The molecules which are endogenous to the other life form such as plants and animals but do
not occur naturally within human body ,such molecules are classed as exogenous molecule for
prospective of drug designing for human beings
Rational Drug Design
• Approximately 2000 small molecules that theoretically exist in our world out of which
1052 are drug like molecules and many of which are purely synthetic and cannot occur
naturally. Thus there is an opportunity to explore the none naturally occurring synthetic
compounds as potential source of lead compound
 Continued…
Combinatorial Chemistry
Synthesis and
Isolation Rapid synthesis of or computer simulation of large no. of different but
structurally related molecules
Combinatorial
Chemistry • Search new leads

Assay • Optimization of target affinity & selectivity.

Development
• ADME properties
High
Throughput • Reduce toxicity and eliminate side effects
Screening

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Continued…
High throughput screening
Synthesis and • It refers to the process by which pharmaceutical companies are able to obtain
Isolation
initial screening data up to 1 million compounds testing against as many as 50
Combinatorial different biological targets/years. This expansion of data collection by several
Chemistry
orders of magnitude is primarily due to advancement in Robotics,
Assay combinatorial chemistry and instrumentation.
Development
• Screening of drug target against selection of chemicals.
High
Throughput • Identification of highly target specific compounds.
Screening

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Assay Development
• Used for measuring the activity of a drug.

Synthesis and • Discriminate between compounds.

Isolation
• Evaluate:
Combinatorial
Chemistry • Expressed protein targets.

• Enzyme/ substrate interactions.

Assay
Development

High
Throughput
Screening
Target Selection Lead Medicinal In Vitro Preclinical Clinical
Discovery Chemistry Studies studies Trials
 MEDICINAL CHEMISTRY
• It’s a discipline at the intersection of synthetic organic chemistry and

Library pharmacology.
Development
• Focuses on small organic molecules (and not on biologics and
SAR Studies
inorganic compounds)

In Silico • Used in
Screening
• Drug discovery (hits)
Chemical
Synthesis
• Lead optimization (hit to lead)
Target Selection Lead Medicinal In Vitro Preclinical Clinical
Discovery Chemistry Studies studies Trials
 Library Development
• Collection of stored chemicals along with associated
Library
Development
database.
SAR Studies
• Assists in High Throughput Screening
In Silico
Screening • Helps in screening of drug target (hit)

Chemical • Based on organic chemistry

Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 SAR Studies
• Helps identify pharmacophore
Library
Development • The pharmacophore is the precise section of the molecule that
is responsible for biological activity
SAR Studies

• Enables to prepare more active compound

In Silico
Screening • Allow elimination of excessive functionality
Chemical
Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 In silico screening
• Computer simulated screening of chemicals
Library
Development
• Helps in finding structures that are most likely to
SAR Studies
bind to drug target.
In Silico
Screening

Chemical • Economic than HTS

Synthesis

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Chemical Synthesis
• Involve production of lead compound in suitable quantity
Library and quality to allow large scale animal and eventual,
Development
extensive human clinical trials
SAR Studies
• Optimization of chemical route for bulk industrial
In Silico production.
Screening
• Suitable drug formulation
Chemical
Synthesis

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 In Vitro Studies
• (In glass) studies using component of organism i.e. test tube
experiments
Drug Affinity • Examples-
and Selectivity
• Cells derived from multicellular organisms
Cell Disease • Subcellular components (Ribosomes, mitochondria)
Models
• Cellular/ subcellular extracts (wheat germ, reticulocyte
MOA extract)
• Purified molecules (DNA,RNA)
Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 PRECLINICAL STUDIES
• The aim of this stage is to satisfy all the requirements that have to be met

Animal models before a new compound is deemed ready to be tested for the first time in
of Disease States
humans. The work falls into four categories

Behavioural • Pharmacological testing

Studies
• Preliminary Toxicological testing
Functional • Pharmacokinetics studies i.e ADME studies
Imaging
• Chemical and pharmaceutical assessment to assess the feasibility of large scale
Ex-Vivo
Studies synthesis and purification.

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 PRECLINICAL STUDIES

• Its experimentation using a whole, living organism.

Animal models of
Disease States • Gives information about,

Behavioural • Metabolic profile

Studies
• Toxicology
Functional
Imaging • Drug interaction

Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Animal models of disease states
• Test conditions involving induced disease or injury similar to
Animal models of
Disease States
human conditions.
Behavioural
Studies • Must be equivalent in mechanism of cause.

Functional • Can predict human toxicity in 71% of the cases.

Imaging
• Eg. SCID mice-HIV
Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Behavioural Studies
• Tools to investigate behavioural results of drugs.
Animal models of
Disease States • Used to observe depression and mental disorders..

Behavioural
• Example:
Studies
• Despair based- Forced swimming/ Tail suspension
Functional • Reward based
Imaging
• Anxiety Based
Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Functional Imaging
• Method of detecting or measuring changes in metabolism,
Animal models of
Disease States blood flow, regional chemical composition, and absorption.

Behavioural • Tracers are used

Studies
• MRI
Functional
Imaging • CT-Scan

Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies Studies Trials
 Ex-Vivo Studies
• Experimentation on tissue in an artificial environment outside the
Animal models of
Disease States organism with the minimum alteration of natural conditions.

Behavioural • Counters ethical issues.

Studies
• Examples:
Functional
Imaging • Measurement of tissue properties

• Realistic models for surgery

Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 CLINICAL TRIALS
• Set of procedures in medical research and drug
Phase-I development to study the safety and efficacy of new drug.

Phase-II
• Essential to get marketing approval from regulatory

authorities.
Phase-III

• May require upto 7 years.

Phase-IV

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Phase I:
• Clinical Pharmacologic Evaluation

• First stage of testing in human subjects.

Phase-I
• 20-50 Healthy Volunteers
Phase-II • Concerned With:

– Human Toxicity.
Phase-III
– Tolerated Dosage Range

Phase-IV – Pharma-cology/dynamics

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Phase II:
• Controlled Clinical Evaluation.

• 50-300 Patients
Phase-I
• Controlled Single Blind Technique

Phase-II • Concerned With:

– Safety
Phase-III
– Efficacy

Phase-IV – Drug Toxicity&Drug Interaction

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Phase III:
• Extended Clinical Trials.

Phase-I • Most expensive & time consuming.

• 250-1000 Patients.

Phase-II • Controlled Double Blind Technique.

• Concerned With:
Phase-III – Safety, Efficacy

– Comparison with other Drugs

– Package Insert
Phase-IV

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
 Phase IV:
• Post Marketing Surveillance.
Phase-I • Designed to detect any rare or long-term adverse effects.

• Adverse Drug Reaction Monitoring

Phase-II

Phase-III

Phase-IV

Target Selection Lead Medicinal In Vitro Preclinical Clinical

Discovery Chemistry Studies studies Trials
ABSTRACT 1
• A review article highlight the use of genomics and proteomics in pharmaceutical drug discovery and
development stating that One of the most pressing issues facing the pharmaceutical industry is the
tremendous dropout rate of lead drug candidates. Genomics and proteomics are today well established in
drug discovery and development, in combination with combinatorial chemistry and high-throughput
screening, are helping to bring forward a matchless number of potential lead compounds. Over the last two
decades, several new genomic technologies have been developed in hopes of addressing the issues of target
identification and lead candidate optimization. Proteomics is a technology platform that is gaining
widespread use in drug discovery and drug development programs. Defined as the protein complement of
the genome, the proteome is a varied and dynamic repertoire of molecules that in many ways dictates the
functional form that is taken by the genome. We focus in this article on recent progress and innovations
utilizing “omics” technologies to identify and validate drug targets, discover disease biomarkers, and design
more effective drugs.( SHARMA NEHA and HARIKUMAR S.L,2013)4
ABSTRACT 2
• A study carried out by Abdul Wadood et al(2014) on the in silico technique illustrates that Hepatitis C virus (HCV) infection
is an alarming and growing threat to public health. The present treatment gives limited efficacy and is poorly tolerated,
recommending the urgent medical demand for novel therapeutics. NS3/4A protease is a significant emerging target for the
treatment of HCV infection. This work reports the complex-based pharmacophore modeling to find out the important
pharmacophoric features essential for the inhibition of both protease and helicase activity of NS3/4A protein of HCV. A seven
featured pharmacophore model of HCV NS3/4A protease was developed from the crystal structure of NS3/4A protease in
complex with a macrocyclic inhibitor interacting with both protease and helicase sites residues via MOE pharmacophore
constructing tool. It consists of four hydrogen bond acceptors (Acc), one hydrophobic (Hyd), one for lone pair or active
hydrogen (Atom L) and a heavy atom feature (Atom Q). The generated pharmacophore model was validated by a test
database of seventy known inhibitors containing 55 active and 15 inactive/least active compounds. The validated
pharmacophore model was used to virtually screen the ChemBridge database. As a result of screening 1009 hits were
retrieved and were subjected to filtering by Lipinski’s rule of five on the basis of which 786 hits were selected for further
assessment using molecular docking studies. Finally, 15 hits of different scaffolds having interactions with important active
site residues were predicted as lead candidates. These candidates having unique scaffolds have a strong likelihood to act as
further starting points in the development of novel and potent NS3/4A protease inhibitors.( Abdul Wadood,et al,2014)6
 )

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