CORRELATION OF DYNAMIC MOLECULAR SHAPE WITH ACTIVITY

IMPROVEMENTS IN CORRELATING BIOLOGICAL ACTIVITY WITH ITS MOST IMPORTANT DETERMINANT, MOLECULAR SHAPE, SHOULD IMPROVE THE EFFICIENCY OF DRUG DISCOVERY. A PARTICULARLY PROMISING METHOD OF SHAPE CORRELATION, "DYLOMMS", HAS BEEN APPLIED AT SK&F TO ELUCIDATE THE GABA UPTAKE RECEPTOR REQUIREMENTS. ITS KEY FEATURES ARE (A) REPRESENTATION OF DYNAMIC MOLECULAR SHAPE AS A POPULATION-WEIGHTED COMPOSITE OF, EFFECTIVELY, COARSE STERIC AND ELECTROSTATIC MAPS OF CONTRIBUTING CONFORMERS AND (B) USE OF PRINCIPAL COMPONENTS TO PERFORM THE DATA REDUCTION IMPLICITLY REQUIRED FOR SUCH AN UNDERDETERMINED PROBLEM AS SHAPE/ACTIVITY CORRELATION. IN PHASE I THE CRUDE CURRENT IMPLEMENTATION OF THIS METHOD WOULD BE CONVERTED INTO AN INTEGRATED, EXPORTABLE SYSTEM, INCORPORATING INTERACTIVE GRAPHICS. IN PHASE II THE APPROACH WOULD BE FURTHER EVALUATED BY APPLICATION TO OTHER SAR PROBLEMS.