title: Discovery of HIV-1 integrase inhibitors through a novel combination of ligand and structure-based drug design.
abstract: Over the past 10 years, classical computer-aided molecular design methods have not been frequently applied for the discovery of novel HIV-1 integrase (IN) inhibitors, due to the intrinsic challenges that this enzyme presents. Therefore, a novel approach that combines the chemical information of known integrase inhibitors with the enzyme's detailed 3D structure in a stepwise fashion is proposed: (I) use of a pharmacophore model (PM), which takes into account in a weighted fashion the chemical features of known ligands, in analogous manner to the to search the Maybridge and the NCI 3D databases; (II) drug-likeness optimization; (III) virtual high-throughput screening of the hits matching the PM query against 1QS4 wild-type IN structure using different Docking/Scoring combinations; (IV) visual inspection and selection of the hits in function of: binding free energies; binding mode type within the active site; retrieval among the best 20% hits in more than 6 Docking/Scoring protocols at the same time. This approach aims at a rational selection of new potential HIV-1 integrase inhibitors.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Padova, 35131 Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Brigo
authors.forename: G Iurcu
authors.initials: GI
authors.lastname: Mustata
authors.forename: J M
authors.initials: JM
authors.lastname: Briggs
authors.forename: S
authors.initials: S
authors.lastname: Moro
mesh_terms: D003198:Computer Simulation; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D008024:Ligands; D019427:HIV Integrase