title: Anti-HIV-1 Activity Prediction of Novel Gp41 Inhibitors Using Structure-Based Virtual Screening and Molecular Dynamics Simulation.
abstract: The fusion of viral and host cell membranes is mediated using gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein. As the HIV-1 enters the host cells, the two helical regions (HR1 and HR2) in the ectodomain of gp41 form a six-helix bundle, which carries the target and viral cell membranes to close proximity. Steps of this process serve as attractive targets for developing HIV-1 fusion inhibitors. Identification of some novel HIV fusion inhibitors with the goal of blocking the formation of the six-helix bundle was accomplished by computer-aided drug design techniques. A virtual screening strategy was employed to recognize small molecules presumably able to bind the gp41 at the internal interface of the NHR helices at the core native viral six-helix. This study was carried out in two stages. In the first stage, a library of more than seven thousand compounds was collected from ZINC, PubChem and BindingDB databases and protein data bank. Key contacts of known inhibitors with gp41 binding site residues were considered as the collecting criteria. In the second stage series of filtering processes were performed on this library in subsequent steps to find the potential gp41 inhibitors. The filtering criteria included pharmacokinetic and ADMET properties as well as in silico anti-HIV-1 prediction. Molecular docking simulation was carried out to identify interactions of the filtered molecules with the key residues in the gp41 binding site. Finally, molecular dynamics simulation indicates the superior inhibitory ability of three selected compounds over the known gp41inhibitor, NB-64.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan/, Iran, 81746-73461.
authors.forename: Saghi
authors.initials: S
authors.lastname: Sepehri
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan/, Iran, 81746-73461.
authors.forename: Lotfollah
authors.initials: L
authors.lastname: Saghaie
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan/, Iran, 81746-73461.|Isfahan Pharmaceutical Research Centre, Isfahan University of Medical Sciences, Isfahan/, Iran, 81746-73461.
authors.forename: Afshin
authors.initials: A
authors.lastname: Fassihi
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology; D056004:Molecular Dynamics Simulation
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; C514787:gp41 protein, Human immunodeficiency virus 1
keywords: PASS; gp41; molecular docking; molecular dynamic; virtual screening