Literature DB >> 27517812

Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase.

Fatima E Agharbaoui1, Ashley C Hoyte2, Stefania Ferro3, Rosaria Gitto3, Maria Rosa Buemi3, James R Fuchs4, Mamuka Kvaratskhelia2, Laura De Luca5.   

Abstract

Through structure-based virtual screening and subsequent activity assays of selected natural products, Lavendustin B was previously identified as an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75). In order to improve the inhibitory potency we have employed in silico-based approaches. Particularly, a series of new analogues was designed and docked into the LEDGF/p75 binding pocket of HIV-1 IN. To identify promising leads we used the Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation (MM-GBSA) method, molecular dynamics simulations and analysis of hydrogen bond occupancies. On the basis of these studies, six analogues of Lavendustine B, containing the benzylamino-hydroxybenzoic scaffold, were selected for synthesis and structure activity-relationship (SAR) studies. Our results demonstrated a good correlation between computational and experimental data, and all six analogues displayed an improved potency for inhibiting IN binding to LEDGF/p75 in vitro to respect to the parent compound Lavendustin B. Additionally, these analogs show to inhibit weakly LEDGF/p75-independent IN catalytic activity suggesting a multimodal allosteric mechanism of action. Nevertheless, for the synthesized compounds similar profiles for HIV-1 inhibition and cytoxicity were highlighted. Taken together, our studies elucidated the mode of action of Lavendustin B analogs and provided a path for their further development as a new promising class of HIV-1 integrase inhibitors.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Entities:  

Keywords:  ALLINI; Computational studies; HIV-1; IN-LEDGF/p75 binding; Integrase; LEDGF/p75

Mesh:

Substances:

Year:  2016        PMID: 27517812      PMCID: PMC5283093          DOI: 10.1016/j.ejmech.2016.07.077

Source DB:  PubMed          Journal:  Eur J Med Chem        ISSN: 0223-5234            Impact factor:   6.514


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