title: Examining structural analogs of elvitegravir as potential inhibitors of HIV-1 integrase.
abstract: Acquired immunodeficiency syndrome (AIDS) is a major health problem in many parts of the world. The human immunodeficiency virus-1 integrase (HIV-1 IN) enzyme has been targeted in HIV patients for therapy. Several integrase inhibitors have been reported, but only elvitegravir (EVG), a new-generation drug, is clinically approved for HIV treatment. In the present work, we investigated two structural analogs of EVG as potential inhibitors of the target molecule, HIV-1 IN. The ligand binding site on HIV-1 IN was identified using Q-SiteFinder, and the HIV-1 IN protein was docked with ligand (EVG and/or analogs) using AutoDock 4. The results suggest that Lys173, Thr125, and His171 are involved in enzyme-substrate binding through hydrogen bonds. Single mutations carried out at Lys173, viz. Lys173Leu (polar > nonpolar) and Lys173Gln (polar > polar), in chain B using PyMOL showed the mutants to have lower binding energy when docked with analog 2, suggesting it to be more stable than analog 1. In conclusion, the mutant HIV-1 IN can bind EVG and its analogs. The physicochemical and pharmacokinetic parameters also show analog 2 to be a promising molecule that can be developed as an alternative to EVG to help overcome the problem of drug resistance by HIV to this inhibitor. Analog 2 may be used as an HIV-1 IN inhibitor with similar potential to that of EVG. Further validation through wet-lab studies, however, is required for future applications.
authors.affiliation: Department of Environment and Sustainable Sciences, Institute of Environment and Sustainable Development, Banaras Hindu University, Varanasi, 221005, India, kavitashah@bhu.ac.in.
authors.forename: Kavita
authors.initials: K
authors.lastname: Shah
authors.forename: Saumya
authors.initials: S
authors.lastname: Gupta
authors.forename: Hirdyesh
authors.initials: H
authors.lastname: Mishra
authors.forename: Prashant K
authors.initials: PK
authors.lastname: Sharma
authors.forename: Amit
authors.initials: A
authors.lastname: Jayaswal
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1