DRUG DISCOVERY

Drug…
Any chemical that produces a change in the
body…
Defined by characteristics:
1. Use or potential use in diagnosis or treatment
of disease
2. Selective in their actions

Need for Drug Discovery
 Unmet Medical Needs:
 New Diseases ,AIDS, Alzheimer’s, obesity
 Low efficacy – dementia, cancer
 Side effects – antipsychotics, antidepressants
 Downstream health cost - (Alzheimer’s; spinal
injury)
 cost of therapy; (Interleukins)
 costs to individual/country; (depression)
 Sustain industrial activity; pharmaceutical
industry employs thousands and makes a massive
contribution to overseas earnings; patent expiry

The changed context of drug
discovery and development
HISTORICAL ASPECTS
 1537-first clinical trial of a novel therapy by
Amboise pare
 1747-James Lind introduced control groups in
experiment, document citrus fruits in the diet
prevent scurvy
 1863- Placebos were first used
 1923-concept of randomisation introduced
 1931-concept of randomisation of patients to
treatment in clinical trials
 1945-ethical impact of clinical trial has become

 1947-thse regulations enshrined in Nuremberg
codex
 1948-1st trial using properly randomised treatment
and control groupss by medical research counsil
 1964- introduction of declaration of Helsinki
 Amended in 1975, 1983, 1989, 1996, 2000, 2002
and 2004

Drug development
 Drug development-The entire process of taking a
newly discovered compound or drug through
regulatory approval to the point of marketing.
 During the development, the new drug or the
compound should adhere to high standards in the
conduct, analysis and interpretation of
preclinical and clinical studies for its smooth
passage through the regulatory approval phase
and eventually to marketing.
 Pathways of drug development are
 Discovery
 Preclinical development
 Clinical development

Choose a disease

Pre-discovery
 Understanding the disease
 Know the underlying cause for the disease
 Try to understand how genes are altered – how they affect
proteins they encode
 How proteins interact with each other in living cells
 How those affected cells change the specific tissue they
are in

How drug works….
 The cells in the body carry out complex molecular
reactions
 A mistake in one reaction might stop an important
protein from being produced or over-produced –
leads to body not producing enough cells (diabetes)
or over production of cells (cancer)
 Drug molecule affect these pathways by interacting
with certain molecules along the pathway – making
them more or less active or changing their activity

Drug discovery
 Drug discovery begins in the laboratory with scientists
of various functional areas working together to identify
cellular and genetic factors that play a role in specific
disease
 Identification of target and resource
 4 steps

Target Selection
Biochemical Classes of Drug Targets
 G-protein coupled receptors - 45%
 enzymes - 28%
 hormones and factors - 11%
 ion channels - 5%
 nuclear receptors - 2%

Target Identification
 Drugs usually act on either cellular or genetic
chemicals in the body, known as targets,
which are believed to be associated with
disease.
 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

Cellular & Genetic Targets
 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 the targets, which are
associated with disease.

Genomics
 The study of genes and their function.
 exploit the findings from the sequencing of the
human and other genomes to find new drug
targets.
 Based on 5 or 10 linked proteins per gene,
proposes that the number of potential drug
targets may lie between 5,000 and 10,000.

Proteomics
 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.
 Target identification with proteomics is performed by
comparing the protein expression levels in normal and
diseased tissues.

Bioinformatics
 It plays a key role in various stages of the drug
discovery process including
 target identification
 computer screening of chemical compounds and
 pharmacogenomics
 Can compare the entire genome of pathogenic and
non-pathogenic strains of a microbe and identify
genes/proteins associated with pathogenism

Target Prioritization/Validation.
 To select targets most likely to be useful in the
development of new treatments for disease,
researchers analyze and compare each drug
target to others based on their association with a
specific disease and their ability to regulate
biological and chemical compounds in the body.
 Tests are conducted to confirm that interactions
with the drug target are associated with a
desired change in the behavior of diseased cells.
 Research scientists can then identify
compounds that have an effect on the target
selected.

Lead Identification.
 A lead compound or substance is one that
is believed to have potential to treat
disease.
 Laboratory scientists can compare known
substances with new compounds to
determine their likelihood of success.
 Leads are sometimes developed as
collections, or libraries, of individual
molecules that possess properties needed
in a new drug.
 Testing is then done on each of these
molecules to confirm its effect on the drug

 Find a promising molecule that could become a drug
 Ways to find a lead compound
o Nature – bacteria, molds, plant extracts
o De Novo – scientists can also create molecules from scratch –
computer modeling
o High throughput screening – test thousands of compounds
against the target to identify any that might be promising
o Biotechnology – scientists can genetically engineer living
systems to produce disease-fighting biological molecules

Lead discovery
• Identification of small molecule modulators
of protein function
• The process of transforming these into high-
content lead series.
Synthesis and Isolation
• Separation of mixture
• Separation of impurities
• In vitro chemical synthesis
• Biosynthetic intermediate

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
Assay Development
• Used for measuring the activity of a drug.
• Discriminate between compounds.
• Evaluate:
• Expressed protein targets.
• Enzyme/ substrate interactions.

High Throughput Screening
• Screening of drug target against selection of
chemicals.
• Identification of highly target specific
compounds.

Lead Optimization.
 Lead optimization compares the properties of
various lead compounds and provides
information to help biopharmaceutical
companies select the compound or
compounds with the greatest potential to be
developed into safe and effective medicines.
 Often during this same stage of development,
lead prioritization studies are conducted in
living organisms (in vivo) and in cells in the
test tube (in vitro) to compare various lead
compounds and how they are metabolized

 Optimization
o Alter the structure of lead candidates to improve
properties
o can make it less likely to interact with other chemical
pathways in the body, thus reducing the potential for
side effects
 “analogues” of the initial leads can be made and
tested
 The biologists test the effects of analogues on
biological systems
 Chemists take this information to make additional
alterations that are then retested by the biologists

 Early safety tests
o Lead compounds go through a series of tests to provide an early
assessment of the safety.
o Scientists test Absorption, Distribution, Metabolism, Excretion
and Toxicological (ADME/Tox) properties, or “pharmacokinetics,”
of each lead.
 Successful drugs must be:
o absorbed into the bloodstream,
o distributed to the proper site of action in the body,
o metabolized efficiently and effectively,
o successfully excreted from the body and
o demonstrated to be not toxic.
 Help researchers prioritize lead compounds early in the
discovery process.
 ADME/Tox studies are performed in living cells, in animals and

Preclinical
 Conversion of drug candidate to a drug product for
human clinical trials
 Lab and animal testing to determine if the drug is safe
enough for human testing
 Testing the lead compounds extensively to determine if
they should move on to testing in humans
 Scientists carry out in vitro and in vivo tests.
 Scientists try to understand how the drug works and
what its safety profile looks like.

In-vitro
 In vitro profiling:
 Biochemical assays (e.g. enzyme activity assays)
Cell culture assays (e.g. cancer cell lines)
Isolated tissue assays (e.g. mucosa model)

Pharmacological & Toxicological
approach
 Pharmacology - Drug action:
 Behaviour and reaction
Physiology
Histopathology
 Toxicology:
 Acute toxicity
Subchronic toxicity
Tissue specific toxicity
Tolerability

THE DRUG DEVELOPMENT
PROCESS Development
Discovery Development
Approximately 10–15 years from idea to marketable drug
Preclinical studies Clinical studies
CHEMISTRY/
PHARMA-
COLOGY
IND* PHASE I PHASE II PHASE III NDA** PHASE IV
Search for
active
substances
Toxicology,
efficacy studies
on various
types of
animals
Regulatory
review
Efficacy
studies on
healthy
volunteers
Clinical studies
on a limited
scale
Comparative
studies on a
large number
of patients
Regulatory
review
Continued
comparative
studies*Investigational
New Drug
Application for
permission to
administer a new drug
to humans
50–150
persons
100–200
patients
500–5,000
patients
Registration,
market
introduction
**New Drug Application
Application for permission
to market
a new drug
KNOWLEDGE
LEVEL
KNOWLEDGE
LEVEL
2–4 YEARS 2–6 MONTHS 3–6 YEARS 1–3 YEARS
TIME SPAN
Early Clinical

THANK YOU