title: Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75.
abstract: The cellular protein lens epithelium-derived growth factor, or transcriptional coactivator p75 (LEDGF/p75), plays a crucial role in HIV integration. The protein-protein interactions (PPIs) between HIV-1 integrase (IN) and its cellular cofactor LEDGF/p75 may therefore serve as targets for the development of new anti-HIV drugs. In this work, a structure-based pharmacophore model for potential small-molecule inhibitors of HIV-1 IN-LEDGF/p75 interaction was developed using the LigandScout software. The 3D model obtained was used for virtual screening of our in-house chemical database, CHIME, leading to the identification of compound CHIBA-3002 as an interesting hit for further optimization. The rational design, synthesis and biological evaluation of four derivatives were then carried out. Our studies resulted in the discovery of a new and more potent small molecule (7, CHIBA-3003) that is able to interfere with the HIV-1 IN-LEDGF/p75 interaction at micromolar concentration, representing one of the first compounds to show activity against these specific PPIs. Docking simulations were subsequently performed in order to investigate the possible binding mode of our new lead compound to HIV-1 IN. This study is a valid starting point for the identification of anti-HIV agents with a different mechanism of action from currently available antiviral drugs.
authors: Department of Medicinal Chemistry, University of Messina, Viale Annunziata, 98168 Messina, Italy. ldeluca@pharma.unime.it
authors: Laura
authors: L
authors: De Luca
authors: Maria Letizia
authors: ML
authors: Barreca
authors: Stefania
authors: S
authors: Ferro
authors: Frauke
authors: F
authors: Christ
authors: Nunzio
authors: N
authors: Iraci
authors: Rosaria
authors: R
authors: Gitto
authors: Anna Maria
authors: AM
authors: Monforte
authors: Zeger
authors: Z
authors: Debyser
authors: Alba
authors: A
authors: Chimirri
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D055808:Drug Discovery; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries; D012984:Software
chemical_list: C544432:CHIBA-3003; D019428:HIV Integrase Inhibitors; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D054852:Small Molecule Libraries; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1