USE OF 3D QSAR METHODOLOGY FOR DATA MINING THE NATIONAL-CANCER-INSTITUTE REPOSITORY OF SMALL MOLECULES - APPLICATION TO HIV-1 REVERSE-TRANSCRIPTASE INHIBITION

A three-dimensional (3D) stereoelectronic pharmacophore developed from a 3D quantitative structure-activity relationship (QSAR) investigatio n formed the basis of the development of a two-phase data-mining metho dology to uncover novel leads to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase at the nonnucleoside binding site . The database searching phase employed a field search for ligand requ irements (such as log P, molecular volume) that were accessible from t he database keys. Next, a 3D database search was performed that used a n automated fitting procedure and the calculation of several binding p arameters. These binding parameters were used to test the hits by a di scriminant function that was previously trained to recognize active fr om inactive analogs. During the structural evaluation phase of the met hodology, conformational properties and complementary receptor feature s of the hits were examined by 2D and 3D evaluations, which were follo wed by molecular modeling investigations. When this method was applied to a test database, an improvement from 6.4% to 100% active analogs w as achieved. (C) 1998 Academic Press.