title: Identification of Binding Mode and Prospective Structural Features of Novel Nef Protein Inhibitors as Potential Anti-HIV Drugs.
abstract: Human immunodeficiency virus (HIV)-negative factor (Nef) protein is an accessory pathogenic factor, which plays a significant role in acquired immune deficiency syndrome (AIDS). Nef deficient HIV virus took a longer time to progress into AIDS. Therefore, targeting Nef protein is considered as a key strategy towards HIV/AIDS treatment. Up-to-date, only few compounds were reported as Nef inhibitors. This has prompted us to provide a first account of an integrated computational framework in order to identify more potential Nef inhibitors. Herein, using a hybrid ligand (shape similarity and pharmacophore) and structure-(molecular docking) based virtual screening approaches combined with molecular dynamics as well as post dynamics analysis, potential new hits were identified as HIV-Nef inhibitors. The top ranked compounds of molecular docking from the shape similarity-based library (ZINC04177596, ∆ Gbind=-28.7482 kcal/mol) and pharmacophore-based library (ZINC36617540, ∆ Gbind=-20.2271 kcal/mol) possess comparatively better binding affinities than the reference molecule, B9 (∆ Gbind= -18.0694 kcal/mol). Both these hits (ZINC04177596 and ZINC36617540) showed similar binding mode at the binding site as like the prototype, B9. Hydrophobic and electrostatic interactions seemed to be the prominent binding forces that hold these ligands at the dimer interface of Nef protein. Finally, a set of chemical structural features that can be used as a guide in the design of novel potential Nef inhibitors is also highlighted herein. We believe that the information gained from this study would be of great importance in the discovery and design of potential small molecules targeting HIV-Nef.
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
authors.forename: Suri
authors.initials: S
authors.lastname: Moonsamy
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
authors.forename: Soumendranath
authors.initials: S
authors.lastname: Bhakat
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Ramesh
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa. soliman@ukzn.ac.za.
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072417:Protein Domains; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D008024:Ligands; D054852:Small Molecule Libraries; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1
keywords: AIDS; HIV-Nef; binding free energy; hybrid ligand and structure-based virtual screening; molecular dynamics