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Technology - From Discovery To Market: Drug Development Process - Part I

Rajendra K. Pandey

(This article is sponsored by The Boston Group)

We already know penicillin, the first antibiotic to be discovered, was found by chance in 1928 when Alexander Fleming accidentally contaminated a Petri dish containing bacteria (Staphylococcus aureus) with the mould that produces this antibiotic (Penicillium).

But in 21st century, discovering and bringing one new drug to the public typically costs a pharmaceutical or biotechnology company nearly $900 million and takes an average of 8 to 10 years. In special circumstances, such as the search for effective drugs to treat AIDS, the Food and Drug Administration (FDA) has encouraged an abbreviated process for drug testing and approval called fast-tracking. The drug discovery and development process is designed to ensure that only those pharmaceutical products that are both safe and effective are brought to market.

How are new drugs discovered?
New drugs begin in the laboratory with chemists, scientists, and pharmacologists that identify cellular and genetic factors that play a role in specific diseases. They search for chemical and biological substances that target these biological markers and are likely to have drug like effects. Out of every 1000 new compounds identified during the discovery process only five are considered safe for testing in human volunteers after preclinical evaluations. After 3 to 6 years of further clinical testing in patients, only one of these compounds is ultimately approved as a marketed drug for treatment.

Design of new drugs
The Information Technology revolution which started at the end of the last millennium has seen computers being introduced into all aspects of our lives and the design of drug molecules is no exception. Computers provide ready access to, and analysis of, the information in these, so-called, combinatorial libraries which was not available to scientists as little as a decade ago. The influence of computational chemistry in drug discovery has grown dramatically in recent years. These have been generated by procedures such as combinatorial chemistry where thousands of compounds can be made using automated facilities. Tools at various levels of theory have been developed and applied to systems ranging from small molecules. to protein complexes and sequence data. Scientists routinely use results from these applications to achieve deeper understanding and to guide the development of new therapeutic agents.

The following sequence of research activities begins the process that results in development of new medicines:

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. Researcher/Scientists use a variety of techniques to identify and isolate a target and learn more about its functions and how these influence disease. Compounds are then identified, which have various interactions with drug targets that are helpful in treatment of a specific disease.

Target Validation
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. Scientists can then identify compounds that have an effect on the target selected.

Lead identification
Lead compounds which show some useful biological activity and which can then be studied further and modified to intensify a desired activity or to reduce undesirable side-effects. Leads are sometimes developed as collections called as libraries of individual molecules. A lead compound or substance is one that is believed to have potential to treat disease. Testing is then done on each of these molecules to confirm its effect on the drug target.

Lead optimization
Lead optimization compares the properties of various lead compounds and provides information to help pharmaceutical and biotechnology 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 and affect the body.

Once these investigations have been completed, the drug development goes through various preclinical and clinical studies. These will be discussed in next issue.

(Rajendra K Pandey received his D.Phil. from the University of Allahabad. He is currently a Scientist with Alnylam Pharmaceuticals, Cambridge, MA. )

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