Drug Discovery Complete Notes

Drug Discovery
Drug Discovery is the complete process of identification/synthesis, validation and successful

testing of particular lead molecule, aimed to be drug against a particular macromolecular target
responsible for a specific disease. Subsequent lead optimization and its pharmacokinetic studies
ending with clinical analyses competes the entire process of drug designing. Armed with the
understanding of the disease, scientists are ready to begin looking for a drug. They search for a
molecule, or “lead compound,” that may act on their target to alter the disease course. If
successful over long odds and years of testing, the lead compound can ultimately become a new
medicine. In the past, most of the drugs have been discovered either by identifying the active
ingredient from traditional remedies or by serendipitous discovery. However, nowadays a new
approach has been utilized to understand how disease and infection are controlled at the
molecular and physiological level to gain insight into the mechanistic aspects of disease. There
are a few ways to find a lead compound:
Nature: Until recently, scientists usually turned to nature to find interesting compounds for
fighting disease. Bacteria found in soil and moldy plants both lead to important new treatments,
for example. Nature still offers many useful substances, but now there are other ways to
approach drug discovery (Eckstein; Madesan, 2002)
De novo/ Bioinformatics: Owing to advances in chemistry and computational biology, scientists

can also create molecules from scratch. They can use sophisticated computer modeling to predict
what type of molecule may work (Anson et al, 2009).
High-throughput Screening (HTS): This process is the most common way that leads are
usually found. Advances in robotics and computational power allow researchers to test hundreds
of thousands of compounds against the target to identify any that might be promising. Based on
the results, several lead compounds are usually selected for further study (Shayne, 2005).
Biotechnology: Scientists can also genetically engineer living systems to produce disease-
fighting biological molecules (Eckstein; Madesan, 2002).
It takes about 10-15 years to develop one new medicine from the time it is discovered to when it
is available for treating patients. The average cost to research and develop each successful drug
is estimated to be $800 million to $1 billion. This number includes the cost of the thousands of
failures: For every 5,000- 10,000 compounds that enter the research and development (R&D)
pipeline, ultimately only one receives the credit.
Drug Discovery pipeline

The important steps involved in the process of drug discovery are as described below.
Target discovery
The identification of new, clinically relevant, molecular targets is of utmost importance to the
discovery of innovative drugs. It has been estimated that up to 10 genes contribute to
multifactoral diseases. Typically these “disease genes” are linked to other 5 to 10 gene products
in physiological circuits which are also suitable for pharmaceutical intervention. If these
numbers are multiplied with the number of diseases that pose a major medical problem in the
industrial world, then there are ~5000 to 10000 potential drug targets. The majority of targets
currently selected for drug discovery efforts are proteins, followed by nucleic acids. Moreover,
the road of target-based drug discovery begins with identifying the function of a possible
therapeutic target and its role in disease.
Target Validation
Involves demonstrating the relevance of the target protein in a disease process/pathogenicity and
ideally requires both gain and loss of function studies. This is accomplished primarily with
knock-out or knock-in animal models, small molecule inhibitors/agonists/antagonists, antisense
nucleic acid constructs, ribozymes, and neutralizing antibodies target validation requires a
demonstration that a molecular target is critically involved in a disease process and that
modulation of the target is likely to have a therapeutic effect.
Lead Identification
Lead compounds are those compounds which contain some but not all desired properties of
Drug. Lead identification phase is usually the follow up of high-throughput screening (HTS), a
method for scientific experimentation especially used in drug discovery and relevant to the fields
of biology and chemistry. Apart from high throughput screening other methods such as virtual
high throughput screening (vHTS), where screening is done using computer-generated models
and attempts to "dock" virtual libraries to a target, are also very important, offering very fast,
reliable and cost effective solution for large drug discovery projects (Schneider and Bohm,
2002).
Lead Optimization
In this process the 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. This process
ideally requires the simultaneous optimization of multiple parameters and is thus a time
consuming and costly step. Hints on how to modify a lead compound can originate from
molecular modeling, quantitative structure-activity relationships, and from structural biology
(structure-based drug design). This is often the tightest bottleneck in drug discovery (Bachmann
and Ghosh, 2001).
Pre-clinical lead development

Drug formulation experiments, in-vivo studies in animals, animal safety studies, drug
metabolism studies and large scale synthesis come under the umbrella of pre-clinical lead
development.
Clinical Trials
The clinical lead development involves 4 phases:
Phase I
In this phase a small group of healthy volunteers (20-80) are selected to assess the safety,
tolerability, pharmacokinetics, and pharmacodynamics of a therapy. It normally include dose
ranging studies so that doses for clinical use can be set/adjusted. There are 3 common kinds of
phase I trials
1) Single Ascending Dose (SAD) studies 2) Multiple Ascending Dose (MAD) studies 3) Food
effect. 80% of drugs fail the Phase I clinical trial.
Phase II
The phase II includes early controlled clinical studies conducted to obtain some preliminary data
on the efficacy of the drug for a particular indication in patients with the disease. This testing
phase also helps determine common short-term side effects and risks associated with the drug.
An overview picture showing various phases of clinical trials.

(insightpharmareports.com)
Phase III
Phase III studies are randomized controlled trials on large patient groups (hundreds to thousands)
aimed at being the definitive assessment of the efficacy of the new therapy, in comparison with
standard therapy. Side effects are also monitored. it is typically expected that there be at least
two successful phase III clinical trials to obtain approval from the Federal Drug Administration
(FDA) USA.
Phase IV
It involves post-launch safety monitoring and ongoing technical support of a drug. This may be
mandated or initiated by the pharmaceutical company. It is designed to detect rare or long term
adverse effects over a large patient population and timescale than was possible during clinical
trials.

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Drug Discovery

Drug Discovery is the complete process of identification/synthesis, validation and successful

De novo/ Bioinformatics: Owing to advances in chemistry and computational biology, scientists

Drug Discovery pipeline

Pre-clinical lead development

An overview picture showing various phases of clinical trials.

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