title: A combination of molecular dynamics and docking calculations to explore the binding mode of ADS-J1, a polyanionic compound endowed with anti-HIV-1 activity.
abstract: The HIV-1 entry process is an important target for the design of new pharmaceuticals for the multidrug therapy of AIDS. A lot of polyanionic compounds, such as polysulfonated and polysulfated, are reported in the literature for their ability to block early stages of HIV-1 replication. Several studies have been performed to elucidate the mechanism of the anti-HIV-1 activity of sulfated polysaccharides and polyanions in general, including binding to cell surface CD4 and interfering with the gp120-coreceptor interaction. Here, we show molecular modeling investigations on ADS-J1, a polyanionic compound with anti-HIV activity that is able to interfere with gp120-coreceptor interactions. Agreeing with experimental data, computer simulations suggested that the V3 loop of gp120 was the preferential binding site for ADS-J1 onto HIV-1. Moreover, mutations induced by the inhibitor significantly changed the stereoelectronic properties of the gp120 surface, justifying a marked drop in the affinity of ADS-J1 toward an ADS-J1-resistant HIV-1 strain.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, I-53100 Siena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Mercedes
authors.initials: M
authors.lastname: Armand-Ugón
authors.forename: Imma
authors.initials: I
authors.lastname: Clotet-Codina
authors.forename: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D009282:Naphthalenesulfonates / Q000378:metabolism / Q000494:pharmacology*; D014227:Triazines / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D009282:Naphthalenesulfonates; D014227:Triazines; C407145:ADS J1