DRUG DESIGN WITH A NEW-TYPE OF MOLECULAR MODELING BASED ON STEREOCHEMICAL COMPLEMENTARITY TO GENE STRUCTURE

Why certain chemical structures and not others are present in nature h as been a recurring question raised by scientists since the first orga nic natural products were characterized. Of equal interest has been el ucidating what structural features within any given class of organic m olecules are responsible for biological activity. Historically, the la ck of satisfactory answers to both questions has relegated the develop ment of biologically active molecules either to serendipity or to exha ustive synthesis and biological testing of large numbers of compounds. This frustration is particularly evident in the pharmaceutical indust ry where the development of drug agonists and antagonists is often tim e consuming, tedious and expensive. Fortunately, this picture is begin ning to change as more information is derived from modern molecular mo deling techniques including characterization of the active sites in en zymes and the ligand binding sites in receptors. Over the past 15 year s 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 stereo chemical relationships with gene structure. These relationships have p roven useful in understanding constraints imposed by nature on the str uctures of small molecules and in correlating structure with activity among certain classes of compounds. Recently, computer graphics and en ergy 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.