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Drug Discovery
Satyansh Kumar Singh, Piyush Yadav, Priyanshu Mishra, Asgar Shameem, Deepak Kumar Yadav.

Department of pharmacy, Prasad institute of technology, jaunpur, (Uttar Pradesh), india.

Abstract: The process of drug development is very expensive process due to high costs of
R&D and human clinical tests. At present a new approach is being tried to understand how
disease and infection are controlled at the molecular and physiological level and to target
specific entities based on the knowledge. The drugs discoveries are based on molecular
biological targets and improve the therapy for disease, wide ranging dosages of the
compounds are introduced to the cell line or animal in order to obtain preliminary efficacy
and pharmacokinetic information. The process of drug discovery involves the identification of
candidates, synthesis, characterization, screening & assay for therapeutic efficacy. Once a
compound has shown its value in these tests, it will begin the process of drug development
prior to clinical trials.

Keywords: Drug discovery: introduction, history of drug discovery, drug

discoveries overview, steps in modern drug discovery, advantages and
disadvantages of drugs discovery, conclusion.

Introduction- “Drugs discovery is the process through which potential new medicines are
identified. It involves a wide range of scientific disciplines, including biology, chemistry and
pharmacology”. In the most drugs have been discovered either by identifying the active
ingredient from traditional remedies or by serendipitous discovery, but we know the disease
controlled by the molecular and physiological level and shape of molecule at atomic level is
well understood. The drugs discovery process mainly involves for the identification of
candidates, characterization, screening and assay for therapeutic efficacy. The process of drug
development is very expensive process due to high costs of R&D and human clinical tests. The
average total cost for only drug development is varies from USD 897 million to USD 1.9 billion.
The typical development time is 10-15 years. The past most drugs have been discovered
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either by identifying the active ingredients from traditional remedies or by serendipitous

discovery. At present a new approach is being tried to understand how disease and infection
are controlled at the molecular and physiological level and to target specific entities based on
the knowledge.

History- Occasionally new drugs are found by accident. The discovery of new pharmaceutical
agents has gone through an evolution over the years and has been adding new technologies
to this increasingly complex process. More frequently they are developed as part of organized
efforts to discover new ways to treat specific disease. The drugs discoveries is based on
molecular biological targets and improve the therapy for disease, example captoprilis is
leader of angiotensin-converting enzyme (ACE) - inhibitors used for treatment of essential
hypertension. Alternative and complementary treatments for hypertension involve use of
angiotension 2 receptor antagonists, losartan was the first compound in this class and was
followed by several additional molecules. Treatment of hypertension by these mechanism
provided physicians with additional options to consider as part of combination therapy or
when other possibilities such as diuretics and/or beta-blockers are unsatisfactory.

Discovered In 1976 – Captoprils

Discovered in 1986 - Valmasartan, telmisartan, and irbesartan
Discovered 1989 - discovered in 1989 M1 and M3 receptor
Discovered 1992 - Imatinib (treatment of myeloid leukemia)
Discovered 2001 - Sitagliptin

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HISTORY OF DRUG DISCOVERY

1970s 1980s
Pre 1919
 RISE OF  COMMERCIALIZATIO
 Herbal drugs BIOTECHNO N OF DRUG
 Serendipitous LOGY DISCOVERY
discoveries  USE OF IT  COMBINATORIAL
CHEMISTRY

1920s, 1930s 1990s

1960s
 Vitamins  Robotics
 Breakdown in
 vaccines etiology  Automation

1940s 1950s

 Antibiotics Era  New technology

 R&D boost due to  Discovery of DNA
WW2

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Drug Discovery Overview

- Drugs discovery effort addresses a biological target that been shown to play a role
in the development of the disease or starts from a molecule with intresting
biological activities
1. Identification of a new potential drug target
2. Rational drug design
3. Modification of an existing drug/potential drug
4. Screening of chemical/macromolecule/organic chemical libraries
5. Biotechnical approaches using the human genome.
6. Combination of known drugs to obtain aided or synergistic effects5.

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Genes

Structure of molecular drug

target

Compound Design

Compound synthesis

Primary screen of
drug target

Cell-based screen for

activity and specificity

Pharmacology Toxicology

Preclinical Drug
Candidate

Fig: Drug discovery

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Steps in Modern Drug Discovery

Drug target Target Lead Lead Pre-clinical

& clinical
Identification Validation Discovery Optimization
Developmement

Step 1: Target identification

Target identification is the first key stage in the drug discovery pipeline. Generally speaking, a
drug target is the specific binding site of a drug in vivo through which the drug exerts its
action6. The process is a chemistry based. Which mean produce compounds for screening.
Approach of identification includes protein expression structural and functional studies and
study of biochemical pathways. For these modes of identification, recently several methods
are available-

1. Sequence Analysis
2. Positional cloning
3. cDNA library generation

Therefore process helps to find a huge number of target identification7. A bio molecule may
be involved in a disease process, but to be a drug target it has to be validated. In other words
shown to be critical in the disease process useful technique available are to validate a target
such as gene knockout and RNA interference.

STEP 2: Target validation

New target validation is the basis of completely new drug exploration and the initial step of
drug discovery.

Research scientists can they identify compounds that have an effect on the target selected.
Test are conducted to confirms that interaction with the drugs target are associated with a
desired change in the behaviour of diseased cells, researcher analyze and compare each drug
target to other based on their association with a specific disease and their ability to regulate

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biological and chemical compounds in the body8. New drug research and development but
also provide more insight into the pathogenesis of target related disease. Basically, the target
validation process might include six steps:

1. Discovering a molecule of interest.

2. Evaluating its potential as a target.
3. Designing a bioassay to measure biological activity.
4. Constructing a high-through put screen.
5. Performing screening to find hits.
6. Evaluating the hits.

Basic research into understanding the fundamentals, essential processes for signalling within
and between cells and their perturbation in condition has been the basic approach for
establishing potential targets suitable for drug intervention9.

STEP3: Lead discovery

This is accomplished primarily with knock-out or knock-in animal models; small molecular
target in vitro usually precedes the validation of the therapeutic concept in vivo; together this
defines in clinical potential. Validation involve studies in molecular target in vitro usually
proceeds with the target protein and modulate its activity10. Synthetic chemicals, peptides,
natural or engineered protein, or antibodies are exposed to the target in a manners that will
detect and isolate those members of the library that interact with and preferably have an
effect on the target11. For example, if the goal is to inhibit a protein that is involved in
activating the expression of a particular gene or set of genes, the assay can include readout to
determine if the expression of the gene is reduced by the compound. The assay can be cell-
based, but more often they are enzymatic assay that can be performed in a high-throughput
manner.

STEP 4: Lead optimization

A lead compound is a compound from a series of related compounds that has some of a
desired biological activity. Leads compounds that survive the initial screening are then
“optimized’” or altered to make them more effective and safer. By changing the structure of a
compound, scientists can give it different properties. For example, they can make it less likely
to interact with other chemical pathway in the body, thus reducing the potential for side
effects.

Researchers begin to think about how the drug will be made, considering formulation (the
recipe for making a drug, including inactive ingredient used to hold it together and allow to

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dissolve at the right time), delivery mechanism (the way the drug is taken – by mouth,
injection, inhaler) and large-scale manufacturing (how you make the drug in large in large
quantities)12.

STEP 5: Pre-clinical and clinical and development

Pre-clinical development: the pre-clinical development includes the following develop

large scale synthesis; animal safety studies; carcinogenicity tests; drug delivery; elimination
and metabolism studies; drug formulation experiments; dose-ranging studies in animals.
Wide ranging dosages of the compounds are introduced to the cell line or animal in order to
obtain preliminary efficacy and pharmacokinetic information.

Clinical development
The NH organizes clinical trial in to 5 different types:

 Treatment trials: test experimental treatments or a new combination of drugs.

 Prevention trials: look for ways to prevent a disease or prevent it from returning.
 Diagnostic trials: find better test or procedures for diagnosing a disease.
 Screening trials: test methods of detecting disease.
 Quality of life trials: explore way to improve comforts & quality of life for individuals
with a chronic illness

Pharmaceutical clinical trials are commonly classified into 4 phases.

1. Phase 0/Micro dosing-

 To obtain prelimary data pharmacokinetics data.
 Sub acute toxicity study in one species by two routes of
administration.
2. Phase 1 –
 20-25 healthy volunteers; duration 6-12 months.
 The aim of a phase 1 trial is to determines the maximum tolerated dose
(MTD) of the new treatment.
3. PHASE 2-
 New action of a marketed drug, start with phase 2.
 Designed to study efficacy and assess dosing requirements

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4. Phase 3 –
 Its a therapeutics confirmatory trial.
 Target population: several 100 are to 3000 patients.
 Duration: takes a long time, up to 5 years.
5. Phase 4-
 Post marketing surveillance (PMS).
 Confirms the efficacy and safety profiles in large population
during practice.
 The ADR can be reported to a formal reporting system such as:
 WHO international system
 USFDA- medwatch
 UK- yellow card system
 India- national pharmacovigilance programme (CDSCO)

Advantages -

1. Patients receive optimal pharmaceutical therapy.

2. Allows for improved availability of medicine because of consistent and known usage
patterns.
3. Enables consistent and predictable treatment from all levels of providers and at all
locations.
4. Helps provide good outcomes because patients are receiving the best treatment
regimen available.

Disadvantages –

1. Guidelines development and maintenance takes much time and effort.

2. STGs may give false of security and discourage ongoing critical thinking.
3. Inaccurate guidelines will provide the wrong information. Often guidelines are based on
existing practices rather than evidenced-based medicine.

Conclusion
The drugs discovery is a time consuming and expensive process, the top twenty
pharmaceutical companies spent – $16 billion on research and development every year, but
recent discovery technologies and strategies have reduced the bottleneck in discovering high
affinity ligand for therapeutic targets. Well designed and effectively executed clinical trials
form the base of therapeutic decisions. The availability of biologics reagents, new methods,
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technologies and computational tools is revolutionizing the way we do biological discovery

and is enabling new approaches to identify noval targets drug discovery and development.

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