title: Non-nucleosidic inhibition of Herpes simplex virus DNA polymerase: mechanistic insights into the anti-herpetic mode of action of herbal drug withaferin A.
abstract: BACKGROUND
  Herpes Simplex Virus 1 and 2 causes several infections in humans including cold sores and encephalitis. Previous antiviral studies on herpes viruses have focussed on developing nucleoside analogues that can inhibit viral polymerase and terminate the replicating viral DNA. However, these drugs bear an intrinsic non-specificity as they can also inhibit cellular polymerase apart from the viral one. The present study is an attempt to elucidate the action mechanism of naturally occurring withaferin A in inhibiting viral DNA polymerase, thus providing an evidence for its development as a novel anti-herpetic drug.
  
  
  RESULTS
  Withaferin A was found to bind very similarly to that of the previously reported 4-oxo-DHQ inhibitor. Withaferin A was observed binding to the residues Gln 617, Gln 618, Asn 815 and Tyr 818, all of which are crucial to the proper functioning of the polymerase. A comparison of the conformation obtained from docking and the molecular dynamics simulations shows that substantial changes in the binding conformations have occurred. These results indicate that the initial receptor-ligand interaction observed after docking can be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favoured.
  
  
  CONCLUSIONS
  We have performed docking and molecular dynamics simulation studies to elucidate the binding mechanism of prospective herbal drug withaferin A onto the structure of DNA polymerase of Herpes simplex virus. Our docking simulations results give high binding affinity of the ligand to the receptor. Long de novo MD simulations for 10 ns performed allowed us to evaluate the dynamic behaviour of the system studied and corroborate the docking results, as well as identify key residues in the enzyme-inhibitor interactions. The present MD simulations support the hypothesis that withaferin A is a potential ligand to target/inhibit DNA polymerase of the Herpes simplex virus. Results of these studies will also guide the design of selective inhibitors of DNA POL with high specificity and potent activity in order to strengthen the therapeutic arsenal available today against the dangerous biological warfare agent represented by Herpes Simplex Virus.
authors.affiliation: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Agrawal
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shandilya
authors.forename: Virendra S
authors.initials: VS
authors.lastname: Bisaria
authors.forename: Durai
authors.initials: D
authors.lastname: Sundar
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004279:DNA, Viral; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D005090:Exodeoxyribonucleases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006561:Herpes Simplex / Q000188:drug therapy; D006566:Herpesviridae Infections / Q000188:drug therapy; D006801:Humans; D056004:Molecular Dynamics Simulation; D019384:Nucleic Acid Synthesis Inhibitors; D011446:Prospective Studies; D018139:Simplexvirus / Q000187:drug effects*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054358:Withanolides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D019384:Nucleic Acid Synthesis Inhibitors; D014764:Viral Proteins; D054358:Withanolides; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus; C009684:withaferin A