title: Molecular docking studies of dithionitrobenzoic acid and its related compounds to protein disulfide isomerase: computational screening of inhibitors to HIV-1 entry.
abstract: BACKGROUND
  Entry of HIV-1 into human lymphoid requires activities of viral envelope glycoproteins gp120 and gp41, and two host-cell proteins, the primary receptor CD4 and a chemokine co-receptor. In addition, a third cell-surface protein called protein disulfide isomerase (PDI) is found to play a major role in HIV-1 entry. PDI is capable of mediating thio-disulfide interchange reactions and could enable the reduction of gp120 disulfide bonds, which triggers the major conformational changes in gp120 and gp41 required for virus entry. In this scenario, inhibition of HIV-1 entry can be brought about by introducing agents that can block thiol-disulfide interchange reaction of cell surface PDI. There have been studies with agents that inhibit PDI activity, but the exact mode of binding remains to be elucidated; this might provide insights to develop new drugs to target PDI. This study attempts to perceive the mode of binding of dithionitrobenzoic acid (DTNB), and its structurally related compounds on PDI enzyme.
  
  
  RESULTS
  We performed molecular docking simulation with six different inhibitors (ligand), which includes DTNB, NSC695265, thionitrobenzoic acid, 2-nitro-5-thiocyanobenzoic acid, 2-nitro-5-sulfo-sulfonyl-benzoic acid and NSC517871 into the redox-active site [C37-G38-H39-C40] of the PDI enzyme and the activity was inferred by redox inhibitory models. All ligands showed favorable interactions and most of them seemed to bind to hydrophobic amino acids Ala34, Trp36, Cys37, Cys40, His39, Thr68 and Phe80. The redox inhibitory conformations were energetically and statistically favored and supported the evidence from wet laboratory experiments reported in the literature.
  
  
  CONCLUSIONS
  We demonstrated that in silico docking experiment can be effectively carried out to recognize the redox inhibitory models of PDI with inhibitor molecules. Interestingly we found that number of docked clusters with each ligand varies in the range of five to eight and conveys that the binding specificity of each inhibitor varies for PDI. We also identified that Cys37 of the enzyme plays an important role in hydrogen bonding with inhibitors. This residue can be considered to being an active site for anti-HIV drug design. Therefore, by inhibiting PDI, one can, not only prevent the viral entry but also circumvent the problem of viral resistance.
authors.affiliation: Bioinformatics Centres of BTISnet at Pondicherry University and IIT Delhi, India. gowtham_15@yahoo.com
authors.forename: Uthaman
authors.initials: U
authors.lastname: Gowthaman
authors.forename: Mannu
authors.initials: M
authors.lastname: Jayakanthan
authors.forename: Durai
authors.initials: D
authors.lastname: Sundar
mesh_terms: D000465:Algorithms; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D004228:Dithionitrobenzoic Acid / Q000737:chemistry*; D015195:Drug Design; D015497:HIV-1 / Q000378:metabolism*; D008024:Ligands; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D019704:Protein Disulfide-Isomerases / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D019380:Anti-HIV Agents; D008024:Ligands; D004228:Dithionitrobenzoic Acid; D019704:Protein Disulfide-Isomerases