title: HIV-1 integrase pharmacophore: discovery of inhibitors through three-dimensional database searching.
abstract: Starting from a known inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN); caffeic acid phenethyl ester (CAPE), a putative three-point pharmacophore for binding of inhibitors to IN was derived. This pharmacophore was used to search the National Cancer Institute three-dimensional (3D) structural database. Out of the open, nonproprietary part of this database, comprising approximately 200000 compounds, 267 structures were found to match the pharmacophore in at least one conformation, and 60 of those were tested in an in vitro assay against HIV-1 IN. Out of these, 19 were found to inhibit both the 3'-processing and strand transfer of IN at micromolar concentrations. In order to test the validity of this pharmacophore, a small 3D database of 152 published IN inhibitors was built. A search in this database yielded a statistically significant correlation of the presence of this pharmacophore and the potency of the compounds. An automated pharmacophore identification procedure performed on this set of compounds provided additional support for the importance of this pharmacophore for binding of inhibitors to IN and hinted at a possible second pharmacophore. The role of aromatic moieties in the binding of ligands to HIV-1 IN through interactions with divalent metal cations, which are known to be necessary for activity of the enzyme, was explored in ab initio calculations.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Nicklaus
authors.forename: N
authors.initials: N
authors.lastname: Neamati
authors.forename: H
authors.initials: H
authors.lastname: Hong
authors.forename: A
authors.initials: A
authors.lastname: Mazumder
authors.forename: S
authors.initials: S
authors.lastname: Sunder
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: G W
authors.initials: GW
authors.lastname: Milne
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D002109:Caffeic Acids / Q000494:pharmacology; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology; D016208:Databases, Factual; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D047309:Flavones; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D008968:Molecular Conformation; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002109:Caffeic Acids; D002867:Chromones; D047309:Flavones; D019428:HIV Integrase Inhibitors; D009838:Oligodeoxyribonucleotides; D019427:HIV Integrase; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; C079163:quercetagetin