Lb. Hendry, DRUG DESIGN WITH A NEW-TYPE OF MOLECULAR MODELING BASED ON STEREOCHEMICAL COMPLEMENTARITY TO GENE STRUCTURE, Journal of clinical pharmacology, 33(12), 1993, pp. 1173-1187
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.