ANALYSIS OF CONFORMATIONAL COVERAGE .2. APPLICATION OF CONFORMATIONALMODELS

It has previously been demonstrated(1) that the low-energy conformatio nal spaces of small- to medium-sized drug molecules can be adequately represented by a small collection of conformations. This paper demonst rates that these representative conformational models consisting of a small collection of conformations (a) suffice for pharmacophore and/or hypothesis generation and (b) return a significant number of valid ge ometric hits from a flexible 3D database search. The resolution of ter se conformational models is quantified using novel metrics that measur e conformational coverage, and the limits of resolution using point co nformers for hypothesis generation are investigated A general methodol ogy for evaluating database search methods is introduced and is used t o demonstrate that point conformations can be used successfully in dat abase searching.