title: Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase.
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.
authors: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM), Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata, I-98168, Messina, Italy; Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA. Electronic address: fagharbaoui@unime.it.
authors: Fatima E
authors: FE
authors: Agharbaoui
authors: Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
authors: Ashley C
authors: AC
authors: Hoyte
authors: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM), Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata, I-98168, Messina, Italy.
authors: Stefania
authors: S
authors: Ferro
authors: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM), Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata, I-98168, Messina, Italy.
authors: Rosaria
authors: R
authors: Gitto
authors: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM), Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata, I-98168, Messina, Italy.
authors: Maria Rosa
authors: MR
authors: Buemi
authors: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
authors: James R
authors: JR
authors: Fuchs
authors: Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
authors: Mamuka
authors: M
authors: Kvaratskhelia
authors: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM), Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata, I-98168, Messina, Italy. Electronic address: ldeluca@unime.it.
authors: Laura
authors: L
authors: De Luca
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062368:meta-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D012459:Salicylates; D062368:meta-Aminobenzoates; C092428:lavendustin B; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: ALLINI; Computational studies; HIV-1; IN-LEDGF/p75 binding; Integrase; LEDGF/p75