title: All-atom models for the non-nucleoside binding site of HIV-1 reverse transcriptase complexed with inhibitors: a 3D QSAR approach.
abstract: Several molecular modeling techniques were used to generate an all-atom molecular model of a receptor binding site starting only from Ca atom coordinates. The model consists of 48 noncontiguous residues of the non-nucleoside binding site of HIV-1 reverse transcriptase and was generated using a congeneric series of nevirapine analogs as structural probes. On the basis of the receptor-ligand atom contacts, the program HINT was used to develop a 3D quantitative structure activity relationship that predicted the rank order of binding affinities for the series of inhibitors. Electronic profiles of the ligands in their docked conformations 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 queries for database searches. A search of the National Cancer Institute's open database identified a lead compound that exhibited moderate antiviral activity.
authors.affiliation: Frederick Biomedical Supercomputing Center, National Cancer Institute-FCRDC, Frederick, Maryland 21702, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gussio
authors.forename: N
authors.initials: N
authors.lastname: Pattabiraman
authors.forename: D W
authors.initials: DW
authors.lastname: Zaharevitz
authors.forename: G E
authors.initials: GE
authors.lastname: Kellogg
authors.forename: I A
authors.initials: IA
authors.lastname: Topol
authors.forename: W G
authors.initials: WG
authors.lastname: Rice
authors.forename: C A
authors.initials: CA
authors.lastname: Schaeffer
authors.forename: J W
authors.initials: JW
authors.lastname: Erickson
authors.forename: S K
authors.initials: SK
authors.lastname: Burt
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007256:Information Systems; D008958:Models, Molecular; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase