title: Insight into the fundamental interactions between LEDGF binding site inhibitors and integrase combining docking and molecular dynamics simulations.
abstract: In recent years, HIV-1 integrase (IN) has emerged as an attractive target for novel anti-AIDS agents. In particular, nonactive-site-binding IN inhibitors would display synergy with current strand-transfer-specific IN inhibitors and other antiretroviral drugs in clinical use. An effective allosteric inhibitory approach would be the disruption of protein-protein interaction (PPI) between IN and cellular cofactors, such as LEDGF/p75. To date, several small molecules have been reported to be inhibitors of the PPI between IN and LEDGF/p75. In this study, we investigated the most relevant interactions between five selected PPI inhibitors and IN comparing them to the naturally occurring IN-LEDGF/p75 complex. We calculated the binding free energies by using the method of molecular mechanics-generalized Born surface area (MM-GBSA). Total energy was decomposed on per residue contribution, and hydrogen bond occupancies were monitored throughout the simulations. Considering all these results we obtained a good correlation with experimental activity and useful insights for the development of new inhibitors.
authors.affiliation: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy. ldeluca@unime.it
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Francesca
authors.initials: F
authors.lastname: Morreale
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation
chemical_list: D019428:HIV Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1