title: Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophore-based virtual screening approach.
abstract: We report the first application of ligand-based virtual screening (VS) methods for discovering new compounds able to inhibit both human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT)-associated functions, DNA polymerase and ribonuclease H (RNase H) activities. The overall VS campaign consisted of two consecutive screening processes. In the first, the VS platform Rapid Overlay of Chemical Structures (ROCS) was used to perform in silico shape-based similarity screening on the NCI compounds database in which a hydrazone derivative, previously shown to inhibit the HIV-1 RT, was chosen. As a result, 34 hit molecules were selected and assayed on both RT-associated functions. In the second, the 4 most potent RT inhibitors identified were selected as queries for parallel VS performed by combining shape-based, 2D-fingerprint and 3D-pharmacophore VS methods. Overall, a set of molecules characterized by new different scaffolds were identified as novel inhibitors of both HIV-1 RT-associated activities in the low micromolar range.
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi Magna Grecia di Catanzaro, Campus Salvatore Venuta, 88100, Catanzaro, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Cardia
authors.forename: Marco
authors.initials: M
authors.lastname: Gaspari
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Luca
authors.initials: L
authors.lastname: Zinzula
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
mesh_terms: D002626:Chemistry, Pharmaceutical; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D010449:Peptide Mapping; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H