title: New scaffolds of natural origin as Integrase-LEDGF/p75 interaction inhibitors: virtual screening and activity assays.
abstract: The disruption of crucial interactions between HIV-1 Integrase and cellular cofactor LEDGF/p75 represents an emerging approach for the design and development of new antiretroviral agents. In this study we report the successful application of a structure-based virtual screening strategy for the discovery of natural hit structures able to inhibit Integrase-LEDGF/p75 interaction. The application of sequential filters (drug-likeness, 3D-pharmacophore mapping, docking, molecular dynamics simulations) yielded a hit list of compounds, out of which 9 were tested in the in vitro AlphaScreen assays and 8 exhibited a detectable inhibition of the interaction between the two proteins. The best inhibitors belong to different chemical classes and could be represent a good starting point for further optimization and structure-activity relationship studies.
authors.affiliation: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy. Electronic address: ldeluca@unime.it.
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Francesca
authors.initials: F
authors.lastname: Morreale
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
mesh_terms: D001681:Biological Assay; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D019429:Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure
chemical_list: D001688:Biological Products; D019428:HIV Integrase Inhibitors; D019429:Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor
keywords: AIDS; CCD; HIV-1; HIV-1 Integrase; IBD; IN; LEDGF; LEDGF/p75; LEDGINs; MD; MM-GBSA; NP; Natural products; PDB; PPI; Protein Data Bank; Protein–protein interaction inhibitors; RMSD; VS; Virtual screening; acquired immunodeficiency syndrome; catalytic core domain; human immunodeficiency virus type 1; integrase; integrase binding domain; lens epithelium-derived growth factor; molecular dynamics; molecular mechanics-generalized Born surface area; natural products; protein–protein interaction; root mean square deviation; virtual screening