THE LOCAL MINIMA METHOD (LMM) OF PHARMACOPHORE DETERMINATION - A PROTOCOL FOR PREDICTING THE BIOACTIVE CONFORMATION OF SMALL, CONFORMATIONALLY FLEXIBLE MOLECULES

Software has been developed for potential energy surface analysis and the local minima,method of pharmacophore determination.(1) LMM is rigo rous and systematic and employs multiple conformations which are the l ocal minima from the potential energy surface af each compound in the data set. It produces a series of possible pharmacophores from a postu lated set of pharmacophore elements. The best pharmacophore is then de termined by performing a comparative molecular field analysis (CoMFA) on each one. The pharmacophore. which produces the most self-consisten t model is deemed the best. Local minima on the gas-phase potential en ergy surface are shown to be a reasonably close-approximation to prote in bound conformations, and these conformations can be found through s ystematic conformational searches followed by minimization of the loca l minima. LMM was used to develop a 3D-QSAR model for dopamine beta-hy droxylase (DBH) inhibitors which was highly predictive (predictive R-2 = 0.71 and standard error of predictions = 0.41). The model predicted that the phenyl and thienyl series of inhibitors were acting as biois osteres. Examination of compounds overlayed in the model indicated a p ossible hydrogen bond acceptor in the DBH active site. Three tyrosine residues previously labeled by mechanism based inhibitors may be actin g as the acceptor and therefore represent excellent candidates for sit e-directed mutagenesis studies.