title: Novel virtual screening protocol based on the combined use of molecular modeling and electron-ion interaction potential techniques to design HIV-1 integrase inhibitors.
abstract: HIV-1 integrase (IN) is an essential enzyme for viral replication and represents an intriguing target for the development of new drugs. Although a large number of compounds have been reported to inhibit IN in biochemical assays, no drug active against this enzyme has been approved by the FDA so far. In this study, we report, for the first time, the use of the electron-ion interaction potential (EIIP) technique in combination with molecular modeling approaches for the identification of new IN inhibitors. An innovative virtual screening approach, based on the determination of both short- and long-range interactions between interacting molecules, was employed with the aim of identifying molecules able to inhibit the binding of IN to viral DNA. Moreover, results from a database screening on the commercial Asinex Gold Collection led to the selection of several compounds. One of them showed a significant inhibitory potency toward IN in the overall integration assay. Biological investigations also showed, in agreement with modeling studies, that these compounds prevent recognition of DNA by IN in a fluorescence fluctuation assay, probably by interacting with the DNA binding domain of IN.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Nevena
authors.initials: N
authors.lastname: Veljkovic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Perovic
authors.forename: Jo
authors.initials: J
authors.lastname: Vercammen
authors.forename: Sean
authors.initials: S
authors.lastname: Hayes
authors.forename: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Myriam
authors.initials: M
authors.lastname: Witvrouw
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Veljko
authors.initials: V
authors.lastname: Veljkovic
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D004279:DNA, Viral / Q000378:metabolism; D015195:Drug Design; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase