ALL-ATOM MODELS FOR THE NONNUCLEOSIDE BINDING-SITE OF HIV-1 REVERSE-TRANSCRIPTASE COMPLEXED WITH INHIBITORS - A 3D QSAR APPROACH

Several molecular modeling techniques were used to generate an all-ato m molecular model of a receptor binding site starting only from Ca ato m coordinates. The model consists of 48 noncontiguous residues of the non-nucleoside binding site of HIV-1 reverse transcriptase and was gen erated using a congeneric series of nevirapine analogs as structural p robes. On the basis of the receptor-ligand atom contacts, the program HINT was used to develop a 3D quantitative structure activity relation ship that predicted the rank order of binding affinities for the serie s of inhibitors. Electronic profiles of the ligands in their docked co nformations were characterized using electrostatic potential maps and frontier orbital calculations. These results led to the development of a 3D stereoelectronic pharmacophore which was used to construct 3D qu eries for database searches. A search of the National Cancer Institute 's open database identified a lead compound that exhibited moderate an tiviral activity.