A molecular field-based similarity approach to pharmacophoric pattern recognition

The use of molecular field-based similarity approaches for obtaining quality molecular alignments and for identifying field-based patterns in bioactive molecules is described. In addition to pairwise similarities, computation of multimolecule similarities affords a means for determining consensus multimolecule alignments. These multimolecule alignments constitute the basis for developing models for the relative binding of bioactive molecules to common protein-binding sites and for the graphical portrayal of molecular field similarity surface plots that identify, visually, molecular regions possessing similar molecular field characteristics. The latter information can then be exploited in the design of molecules that mimic appropriate characteristics of these highly similar steric and electrostatic domains. Regions with low steric and electrostatic similarity in suitably aligned sets of bioactive molecules represent tolerant domains where new structural motifs can be incorporated without significant reductions in activity. To illustrate the potential applicability of the actual molecular field-based similarity approaches to the design of bioactive molecules, a study on a set of HIV-1 protease inhibitors is presented.