HIV-1 integrase is a unique promising component of the viral replication cycle, catalyzing the integration of reverse transcribed viral cDNA into the host cell genome. Generally, IN activity requires both viral as well as a cellular co-factor in the processing replication cycle. Among them, the human lens epithelium-derived growth factor (LEDGF/p75) represented as promising cellular co-factor which supports the viral replication by tethering IN to the chromatin. Due to its major importance in the early steps of HIV replication, the interaction between IN and LEDGF/p75 has become a pleasing target for anti-HIV drug discovery. The present study involves the finding of novel inhibitor based on the information of dimeric CCD of IN in complex with known inhibitor, which were carried out by applying a structure-based virtual screening concept with molecular docking. Additionally, Free binding energy, ADME properties, PAINS analysis, Density Functional Theory, and Enrichment Calculations were performed on selected compounds for getting a best lead molecule. On the basis of these analyses, the current study proposes top 3 compounds: Enamine-Z742267384, Maybridge-HTS02400, and Specs-AE-848/37125099 with acceptable pharmacological properties and enhanced binding affinity to inhibit the interaction between IN and LEDGF/p75. Furthermore, Simulation studies were carried out on these molecules to expose their dynamics behavior and stability. We expect that the findings obtained here could be future therapeutic agents and may provide an outline for the experimental studies to stimulate the innovative strategy for research community.
Keywords: ADME – Absorption, Distribution, Metabolism, Excretion; AIDS; AIDS – Acquired immunodeficiency syndrome; CCD – catalytic core domain; CNS – Central Nervous System; DFT – Density Functional Theory; HIV-1 integrase; IBD – IN-binding domain; IFD – Induced fit docking; IN – Integrase; LEDGF/p75 – lens epithelium-derived growth factor; LEDGINs – lens epithelium-derived growth factor Integrase Inhibitor; MDS – Molecular dynamics simulation; MM-GBSA – Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation; PPI – protein-protein interaction; VS – Virtual screening; human LEDGF/p75; molecular docking and simulation; protein–protein interaction; virtual screening.