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.

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.