ANALYSIS OF CONFORMATIONAL COVERAGE .2. APPLICATION OF CONFORMATIONAL MODELS

It has previously been demonstrated(1) that the low-energy conformational spaces of small- to medium-sized drug molecules can be adequately represented by a small collection of conformations. This paper demonstrates 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 geometric hits from a flexible 3D database search. The resolution of terse conformational models is quantified using novel metrics that measure conformational coverage, and the limits of resolution using point conformers for hypothesis generation are investigated A general methodology for evaluating database search methods is introduced and is used to demonstrate that point conformations can be used successfully in database searching.