Any chemical that produces a change in the
Defined by characteristics:
1. Use or potential use in diagnosis or treatment
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
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
1537-first clinical trial of a novel therapy by
1747-James Lind introduced control groups in
experiment, document citrus fruits in the diet
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
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
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
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
How drug works….
The cells in the body carry out complex molecular
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 begins in the laboratory with scientists
of various functional areas working together to identify
cellular and genetic factors that play a role in specific
Identification of target and resource
Drugs usually act on either cellular or genetic
chemicals in the body, known as targets,
which are believed to be associated with
Scientists use a variety of techniques to
identify and isolate individual targets to learn
more about their functions and how they
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.
The study of genes and their function.
exploit the findings from the sequencing of the
human and other genomes to find new drug
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.
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
Target identification with proteomics is performed by
comparing the protein expression levels in normal and
It plays a key role in various stages of the drug
discovery process including
computer screening of chemical compounds and
Can compare the entire genome of pathogenic and
non-pathogenic strains of a microbe and identify
genes/proteins associated with pathogenism
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
A lead compound or substance is one that
is believed to have potential to treat
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 –
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
• 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
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
• Used for measuring the activity of a drug.
• Discriminate between compounds.
• Expressed protein targets.
• Enzyme/ substrate interactions.
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
o Alter the structure of lead candidates to improve
o can make it less likely to interact with other chemical
pathways in the body, thus reducing the potential for
“analogues” of the initial leads can be made and
The biologists test the effects of analogues on
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
ADME/Tox studies are performed in living cells, in animals and
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.
Pharmacological & Toxicological
Pharmacology - Drug action:
Behaviour and reaction
Tissue specific toxicity
THE DRUG DEVELOPMENT
Approximately 10–15 years from idea to marketable drug
Preclinical studies Clinical studies
IND* PHASE I PHASE II PHASE III NDA** PHASE IV
on a limited
studies on a
administer a new drug
**New Drug Application
Application for permission
a new drug
2–4 YEARS 2–6 MONTHS 3–6 YEARS 1–3 YEARS
1.Candidate drug emerges from a drug discovery programme. Candidate must complete a series of evaluations of its potential safety and efficacy and must be amenable to mass production.for each drug completing the pathway,5000-10000 are evaluated in the discovery phase
There are various ways of illustrating the R&D process – this is one. We see, among other things, how knowledge about a drug increases during the course of the process, but that upon market introduction, there is still a great deal to be learned about how the drug works in the body. Developing a new drug is a complex and costly process.
If everything goes according to plan, a new drug will be ready approximately ten years after the work was first begun. We are working to shorten this time to eight years.
Pharmaceutical companies are constantly striving to shorten the time from idea to finished pharmaceutical product. At the same time, the demands on documentation continue to rise.