title: Is the conformational flexibility of piperazine derivatives important to inhibit HIV-1 replication?
abstract: The conserved binding site of HIV-1 gp120 envelope protein, an essential component in the viral entry process, provides an attractive antiviral target. The structural similarities between two piperazine derivatives: PMS-601, showing a dual activity for anti-PAF and anti-HIV activity, and BMS-378806, known to inhibit HIV-1 gp120, motivated us to merge important structural features of the two compounds. Novel piperazine derivatives were synthesized and evaluated in vitro concerning their ability to inhibit HIV-1 replication in in vitro infected lymphocytes. We described an approach that combines molecular docking, molecular dynamics, MM-PBSA calculations and conformational analysis to rationally predict piperazine derivatives binding mode with HIV-1 gp120. We also inquired about the conformational adaptability of the molecules, upon complex formation, and its importance to their respective inhibitory activity. The analysis suggested that the impact of the flexibility of these molecules revealed to be more important, in the context of drug design, than it has generally been assumed. These new insights at the atomic level might be useful to design inhibitors with improved antiviral activity.
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086, CNRS, 15 rue Jean Antoine de Baïf, F-75205 Paris, France. ca.teixeira@ua.pt
authors.forename: Cátia
authors.initials: C
authors.lastname: Teixeira
authors.forename: Nawal
authors.initials: N
authors.lastname: Serradji
authors.forename: Souad
authors.initials: S
authors.lastname: Amroune
authors.forename: Karen
authors.initials: K
authors.lastname: Storck
authors.forename: Christine
authors.initials: C
authors.lastname: Rogez-Kreuz
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.forename: Florent
authors.initials: F
authors.lastname: Barbault
authors.forename: François
authors.initials: F
authors.lastname: Maurel
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; C477855:BMS-378806; D015699:HIV Envelope Protein gp120; D010879:Piperazines; C514793:gp120 protein, Human immunodeficiency virus 1; D000077489:Piperazine
keywords: BMS-378806; Conformational flexibility; Docking and molecular dynamics; HIV-1 gp120; Piperazine derivatives