Drug design with a new type of molecular modeling based on stereochemical complementarity to gene structure.

Abstract

Why certain chemical structures and not others are present in nature has been a recurring question raised by scientists since the first organic natural products were characterized. Of equal interest has been elucidating what structural features within any given class of organic molecules are responsible for biological activity. Historically, the lack of satisfactory answers to both questions has relegated the development of biologically active molecules either to serendipity or to exhaustive synthesis and biological testing of large numbers of compounds. This frustration is particularly evident in the pharmaceutical industry where the development of drug agonists and antagonists is often time consuming, tedious and expensive. Fortunately, this picture is beginning to change as more information is derived from modern molecular modeling techniques including characterization of the active sites in enzymes and the ligand binding sites in receptors. Over the past 15 years another approach has emerged based upon a series of discoveries made in our laboratories with molecular models. Namely, many biologically active small molecules have been found to possess complementary stereochemical relationships with gene structure. These relationships have proven useful in understanding constraints imposed by nature on the structures of small molecules and in correlating structure with activity among certain classes of compounds. Recently, computer graphics and energy calculations have confirmed salient observations lending credence to what promises to be a powerful and rapidly evolving technology for designing new safe and effective drugs.