MULTICONFORMATIONAL COMPOSITE MOLECULAR-POTENTIAL FIELDS IN THE ANALYSIS OF DRUG-ACTION .1. METHODOLOGY AND FIRST EVALUATION USING 5-HT ANDHISTAMINE ACTION AS EXAMPLES

The quality of molecular electrostatic maps generated by non-quantum m echanical methods has been improved using extended electron distributi ons. Further simplification has been achieved by distilling these maps down to their energy extrema. A new means of defining surface interac tion has been added and the resulting composite map has been plotted f or a limited number of low-lying conformers of a series of agonists an d antagonists of the H-2 and H-3 receptors and 5-HT1A and 5-HT1D recep tors. The results from the cross-comparison of these maps indicate the ir ability to distinguish the specific receptor. Interesting consequen ces of the method are that structural overlay is irrelevant, that seve ral conformations may contribute to the overall binding pattern and th at lesser pharmacological activities may be deduced from the results.