title: Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor.
abstract: The search of small molecules as protein-protein interaction inhibitors represents a new attractive strategy to develop anti-HIV-1 agents. We previously reported a computational study that led to the discovery of new inhibitors of the interaction between enzyme HIV-1 integrase (IN) and the nuclear protein lens epithelium growth factor LEDGF/p75.(1) Herein, we describe new findings about the binding site of LEDGF/p75 on IN employing a different computational approach. In this way further structural requirements, helpful to disrupt LEDGF/p75-IN binding, have been identified. The main result of this work was the exploration of a relevant hydrophobic region. So we planned the introduction of suitable and simple chemical modifications on our previously reported 'hit' and the new synthesized compounds were subjected to biological tests. The results obtained demonstrate that the hydrophobic pocket could play a key role in improving inhibitory efficacy thus opening new suggestions to design active ligands.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina Viale Annunziata, I-98168 Messina, Italy. ldeluca@unime.it
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Stefano
authors.initials: S
authors.lastname: Agnello
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1