resumo
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. (C) 2013 Elsevier Inc. All rights reserved.
palavras-chave
FREE-ENERGY DECOMPOSITION; CD4 RECEPTOR-BINDING; ENVELOPE GLYCOPROTEINS; ENTRY INHIBITORS; VIRAL ENVELOPE; LIQUID WATER; FORCE-FIELD; GP120; MODELS; DOCKING
categoria
Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology
autores
Teixeira, C; Serradji, N; Amroune, S; Storck, K; Rogez-Kreuz, C; Clayette, P; Barbault, F; Maurel, F
nossos autores
Cátia Teixeira
Bolseiro de pós-DoutoramentoGrupos
agradecimentos
We are grateful for the financial support from Fundacao para a Ciencia e a Tecnologia (Portugal) for the PhD fellowship SFRH/BD/22190/2005 to Catia Teixeira. The authors thank the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) for grant no. 07-341 (contrat d'initiation d'une recherche). Thank you to Pr. M. Malacria (Institut Parisien de Chimie Moleculaire, Universite Pierre et Marie Curie, France) for technical NMR assistance. This work has benefited from the facilities and expertise of the Small Molecule Mass Spectrometry platform of IMAGIF (Centre de Recherche de Gif - www.imagif.cnrs.fr).