The document outlines the complex drug discovery and development process, highlighting that it involves identifying new medications, rigorous testing, and regulatory compliance, with a high cost associated with bringing drugs to market. It details various stages such as target identification, validation, lead identification, and optimization, emphasizing that only a small fraction of tested compounds ultimately become marketable products. Additionally, modern advances like high-throughput screening and bioinformatics are discussed as key components that enhance the efficiency of the drug discovery process.

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Drug Discovery Process
Dr. A.K. Singh
Professor
MMCP, MM(DU), Mullana

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Drug Discovery and Drug Development
• Drug discovery is the process by which new candidate
medications are discovered
• Drug development is the process of bringing a new
pharmaceutical drug to the market once a lead compound
has been identified through the process of drug discovery

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INTRODUCTION
•Drug development process involves rigorous testing
and optimization of selected compounds to identify
the drug that is most effective.
•This testing is done in cells(in vitro) or in animals(in
vivo) to study the metabolism and to produce a
product that is safe and has passed all regulatory
requirements.

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 Not every compound that is tested in laboratory is marketed ; it has to
undergo several stages of development called drug development.
 The development of new drugs is a complex and costly process
because many compounds that are tested are thrown away at the
preliminary stage only.
 To innovate a new drugs a company needs to begin with many
thousands of compounds.
 The average cost for research and development for each efficacious
drug is likely to be $900 million to $2 billion.
 R & D task involves discovery(preclinical studies) and development
(clinical studies) of New Chemical Entities(NCEs)/(NMES).

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 About 10,000 NCEs investigated to potentially
treat disease , only 250 make it to animal testing
stage, and approximately 5-10 would qualify for
testing in humans.
 Only 1-2 products of the original 10,000 NCEs
result in a marketable product.

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DEFINITIONS
• DRUG- According to WHO- Drug is any substance or product that is
used for or intended to be used to modify or explore physiological
systems or pathological states for the benefit of the recipient.
• NEW DRUG- According to Rule 122E-
1.Any new substance proclaimed for therapeutic use
2.An already approved drug with modified/ new therapeutic claims,
indication, dosage forms or routes of administration
3. All vaccines and recombinant R-DNA derived products
4. A New drug shall continue to be considered as new drug for four
years.

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MODERN DAY DRUG
DEVELOPMENT

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Stages of Drug Development
1. Target identification
2. Target validation
3. Lead identification
4. Lead optimization
5. Product characterization
6. Formulation and development
7. Preclinical research
8. Investigational New Drug
9. Clinical trials
10. New Drug Application
11. Approval

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DRUG DISCOVERY PHASE
• Drug discovery is a process, which aims at identifying a
compound therapeutically useful in treating and curing a
disease.
• The process of drug discovery involves the identification of
the candidates, Synthesis, characterisation, screening, and
assays for therapeutic efficacy.

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STEPS IN DRUG DISCOVERY
1.Step 1- Drug Target Identification
2.Step 2- Target Validation
3.Step 3- Lead Identification
4.Step 4- Lead Optimization

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STEP1: TARGET IDENTIFICATION
• It is the key stage in the drug discovery.
• A drug target is the specific binding site of a drug in vivo through which the drug exerts its
action.
• The first step in the discovery of a drug is identification of the biological origin of a disease, and
the potential targets for intervention.
•Target identification starts with isolating the function of a possible therapeutic target (gene/nucleic
acid/protein) and its role in the disease.
•Identification of the target is followed by characterization of the molecular mechanisms addressed
by the target. An ideal target should be efficacious, safe, meet clinical and commercial
requirements and be druggable.
•The techniques used for target identification may be based on principles of molecular biology,
biochemistry, genetics, biophysics, or other disciplines.

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• A specific drug target might have the following characteristics:
1. The drug target is a biomolecule(s), normally a protein that could exist in isolated or
as a complex modality.
2. The biomolecules have special sites that match others.
3.The biomolecular structure might change when the biomolecule binds to drug and
the changes in structure normally are reversible .
4. Following the change in the biomolecule’s structure various physiological responses
occur and induce regulation of the cell, organ, tissue, or body status.
5. The physiological responses triggered by the changes in biomolecule structure play a
major role in complex regulation and have a therapeutic effect on pathological
conditions.
6. The expression, activity, and structure of the biomolecule might change over the
duration of the pathological process.

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EXAMPLE
• The knowledge that breast cancer is often estrogen-sensitive led to the
development of aromatase inhibitors such as anastrozole , which
prevents estrogen synthesis.

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Various targets of drug action
The majority of drug targets are :
a)G-protein coupled receptors
b)Nuclear receptors
c)Ion channels
d)Enzymes

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Target identification strategies
 Gene Expression profiling: Genomics
 Focussed Proteomics
 Metabolic pathways analysis: Molecular Biology

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STEP2: TARGET VALIDATION
• Target validation is the process of demonstrating the
functional role of the identified target in the disease
phenotype.
• It is the process by which the predicted molecular target is
verified.
• New drug target validation might be of great help not only to
new drug research and development but also provide more
insight into the pathogenesis of target related diseases.

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Steps of Target Validation
• Basically, the target validation process might include five
steps:
1.Discovering a biomolecule of interest.
2. Evaluating its potential as a target.
3. Designing a bioassay to measure its biological activity.
4. Constructing a high-throughput screening(hts).
5. Performing screening to find lead compounds.

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STEP3: LEAD IDENTIFICATION
•A Lead compound in drug discovery is a chemical
compound that has pharmacological or biological
activity.
•Also called developmental candidates, because the
discovery and selection of lead compounds occurs
prior to preclinical and clinical development of the
candidate.

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Criteria for leads
 Pharmacokinetic properties - metabolic stability and toxicological
aspects.
Pharmacodynamic properties - efficacy, potency, selectivity
 Physiochemical properties - water solubility, chemical stability
Chemical optimization potential - ease of chemical synthesis and
derivatization.
 Patentability

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Methods of lead Identification
1. Random Screening-
All compound including synthetic chemicals, natural products of plant,
marine and microbial origin from a given series is tested.
These are screened randomly in the hope of finding a compound with a
specific biological activity.
This approach entered a new dimension with combinatorial chemistry &
high through-put screening that allows considering the chemistry & the
screening in an automated manner.
Antibiotics like streptomycin and tetracycline have been found out by this
method.

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2. Non-random Screening- it is a modified form of random screening
which was developed because of budgetary and manpower restrictions. In
this method only such compound with similar chemical structure are
tested.
3. Clinical observation- Many a time a drug possess more than one
pharmacological activities. The main activity is called as Therapeutic effect
and while the rest of the action is called as side effects. Such compound
may be used as lead compound for structural modification to improve
potency of secondary effects.
4. Drug metabolism studies-Structural modifications are done in drug
molecule by the enzymes to increase its polarity. The discovery of
sulfanilamide is reported through the metabolic studies of prontosil.

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EXAMPLE OF A LEAD (TAMIFLU) BINDING TO
THE PROTEIN TARGET (NEURAMINIDASE)

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RECENT ADVANCES IN DRUG
DISCOVERY

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HIGH-THROUGHPUT SCREENING TECHNIQUE
(HTS)
HTS is the process of assaying a large number of potential effectors of
biological activity against targets (a biological event).
The methods of HTS are applied to the screening of genomics, proteins,
and peptide libraries.
The goal of HTS is to accelerate drug discovery by screening large
libraries often composed of hundreds of thousands of compounds (drug
candidates) at a rate that may exceed 20,000 compounds per week.

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GENOMICS
• Genomics is the study of entire genomes. The intention of executing the
sequencing and analysis of the entire human genome was to enable more
rapid and effective identification of disease-associated genes and thereby
provide it to drug companies with pre-validated targets.

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PROTEOMICS
• Proteomics is the systematic high-throughput separation and
characterization of proteins within biological systems. it is at the protein
level that disease processes become manifest and at which most drugs
act.

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BIOINFORMATICS
• Bioinformatics is the use of IT in biotechnology for the data storage, data
warehousing and analyzing the DNA sequences. They can now contribute
to lead discovery by exploiting high throughput methods of structure
determination that provide powerful approaches to screening of
fragment binding.

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STEP4: LEAD OPTIMIZATION
• Lead optimization is a process that begins with a compound that displays
an interesting biological action and ends with the identification of the best
analog.
• Molecules are chemically modified and subsequently characterized in
order to obtain compounds with suitable properties to become a drug.
• Leads are characterized with respect to pharmacodynamic properties such
as efficacy and potency in vitro and in vivo, Physiochemical properties,
pharmacokinetic properties, and toxicological aspects.

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• Potency - refers to the amount of drug required for its specific effect to
occur.
• Efficacy - measures the maximum strength of the effect itself, at saturating
drug concentrate ions.
• Pharmacokinetics - It explains about “What the body does to the drug”. It
often divided into areas examining the extent and rate of absorption,
distribution,metabolism, and excretion (ADME).
• Pharmacodynamics– It determines the biochemical and physiological
effects of drugs, the mechanism of drug action and the relationship
between drug concentration and effect. It explains about “ What the drug
does to the body”.

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CONT….
• This process ideally requires the simultaneous optimization of
multiple parameters and is thus a time consuming and is a
costly step.
• This is often the tightest bottleneck in drug discovery.
However, by turning a biologically active chemical into an
effective and safe drug, lead optimization contributes
essentially towards added value in the drug discovery process.

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When any new drug molecule shows a promising
therapeutic activity, then the molecule is characterized by
its size, shape, strength, weakness, use, toxicity, and
biological activity.
Early stages of pharmacological studies are helpful to
characterize the mechanism of action of the compound.
5. PRODUCT CHARACTERIZATION

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6. FORMULATION AND DEVELOPMENT
The physicochemical properties of active pharmaceutical
Ingredient (APIs) are characterized to produce a bioavailable,
stable and optimal dosage form for a specific administration
route.

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STEP 7: PRE-CLINICAL DEVELOPMENT
• The aim of preclinical development is to satisfy all the requirements that
have to be met before a new compound is deemed ready to be tested
for the first time in humans.
• Mainly done on Mice, Rabbit, Rat, Monkeys.
• It is divided into four main categories:
1.Safety Pharmacology- Pharmacological testing to check that the drug
does not produce any obviously hazardous acute effects, such as
bronchoconstriction, cardiac dysrhythmias, blood pressure changes and
ataxia.

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2. Preliminary toxicological testing to eliminate genotoxicity and to
determine the maximum non-toxic dose of the drug (usually when given
daily for 28 days, and tested in two species).
As well as being checked regularly for weight loss and other gross changes,
the animals so treated are examined minutely.
Post mortem at the end of the experiment to search for histological and
biochemical evidence of tissue damage.
3. Pharmacokinetic and pharmacodynamic (PK/PD) testing.
4. Chemical and pharmaceutical development to assess the feasibility of
large-scale synthesis and purification, to assess the stability of the
compound under various conditions and to develop a formulation suitable
for clinical studies.

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GOOD LABORATORY PRACTICE
• Much of the work of preclinical development, especially that
relating to safety issues, is done under a formal operating code,
known as Good Laboratory Practice (GLP), which covers such
aspects as record-keeping procedures, data analysis, instrument
calibration and staff training.
• The aim of GLP is to eliminate human error as far as possible and
to ensure the reliability of the data submitted to the regulatory
authority, and laboratories are regularly monitored for compliance
to GLP standards.

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8. IND APPLICATION
• When a company in India wants to manufacture/ import a new
drug it has to apply to seek permission from the licensing
authority (DCGI) by filing in Form 44 also submitting the data as
given in Schedule Y of Drugs and Cosmetics Act 1940 and Rules
1945.
• Form 44- Application for Permission to undertake clinical
trial/Manufacture/Import of New Drugs with details of
documents to be submitted along with prescribed fees.

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