title: Molecular basis and potential activity of HIV-1 reverse transcriptase toward trimethylamine-based compounds.
abstract: Reverse transcriptase (RT) inhibitors are currently used to treat human immunodeficiency virus (HIV)-1 infections. In this work, novel triethylamine derivatives were designed and studied by rigid and flexible docking and molecular dynamics (MD) approaches. An apo form of HIV-1 RT was also studied by MD simulation to analyze comparative response of protein in ligand-bound and ligand-unbound forms. Among newly designed HIV-1 RT inhibitors, compound HIV104 was the most potent inhibitor considering different docking results. Molecular docking results were further validated by MD simulations of an HIV-1 RT/HIV104 complex using two independent software (Discovery Studio Client 3.1 and GROMACS) to perform comparative analysis. Results suggest that hydroxyl and carboxyl groups present at -R1position in compounds favored strong H-bond contacts as well as good interaction energy profile. Our MD results are consistent with the observations that conformational dynamics between the thumb and finger subdomains of HIV-1 RT controls its dynamics on substrate binding and subsequent activity. MD studies of HIV-1 RT/HIV104 provide insight into interrelatedness of residue scale interactions and global conformational change and also hint at the complex nature of allosteric inhibition. Thus, the results obtained from this study facilitate the design of potent HIV-1 RT inhibitors.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Gdansk, Poland.
authors.forename: Monikaben
authors.initials: M
authors.lastname: Padariya
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Gdansk, Poland.
authors.forename: Umesh
authors.initials: U
authors.lastname: Kalathiya
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Gdansk, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Baginski
mesh_terms: D004305:Dose-Response Relationship, Drug; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D008744:Methylamines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C023336:trimethylamine
keywords: HIV-1; docking; molecular dynamics; reverse transcriptase; triethylamine analogs