International Union of Pure and Applied Chemistry

Molecular diversity, biological diversity and the search for new drugs*

Robert P. Borris and Steven J. Gould

Department of Natural Products Drug Discovery, Merck Research Laboratories, P.O.Box 2000, P. Roy Vagelos Research and Development Center Rahway, New Jersey 07065, USA.
E-mail: [email protected]

Abstract: The success of the drug discovery process is often a function of the diversity of chemotypes examined. Natural products screening represents a potential source of organic chemicals of unparalleled diversity. To effectively realize this potential requires use of a selection strategy tailored to the needs of the individual screening program. Historically, plants and microorganisms have been extraordinarily rich sources of medicinally and agriculturally useful compounds. Interest in these sources of new bioactive molecules continues to the present time. In recent years, the evaluation of insects and Marine invertebrates as sources of biologically active compounds has added to the array of new chemotypes. While the efficiencies of modern screening methods allow for the cost effective evaluation of vast numbers of samples, the cost of acquiring and processing natural products, particularly macro-organisms, is substantial relative to other sources of molecular diversity. A successful drug discovery program must then aim to evaluate the broadest diversity of relevant chemical classes in the minimum number of samples and least time. To achieve this goal, a careful assessment must be made of each source of molecular diversity, natural and man-made, and a proper balance of sources established. An evaluation of the ecological/environmental ramifications of collecting organisms from natural populations for screening operations and pre-development studies is an integral part of this assessment. While the screening of natural products, requiring a very small sample, is a practical endeavour, the realities of obtaining sufficient quantities of compound from natural populations of macroorganisms to support product development and eventual sale are often problematic. Alternative methods of producing interesting compounds, including synthesis, cell culture and agriculture, may be required in order to minimize the ecological impact of these discoveries. While our environmental concerns often focus on the direct impact of this research, they extend far beyond the scope of these studies, fostering the preservation and sustainable utilization of the natural habitats of our collaboratoring source countries. This presentation will contrast the attributes of the molecular diversity obtainable from a variety of natural and manmade sources, with illustrative examples from recent experience.

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