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, 12 Suppl 13 (Suppl 13), S22

Non-nucleosidic Inhibition of Herpes Simplex Virus DNA Polymerase: Mechanistic Insights Into the Anti-Herpetic Mode of Action of Herbal Drug Withaferin A

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Non-nucleosidic Inhibition of Herpes Simplex Virus DNA Polymerase: Mechanistic Insights Into the Anti-Herpetic Mode of Action of Herbal Drug Withaferin A

Abhinav Grover et al. BMC Bioinformatics.

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.

Figures

Figure 1
Figure 1
Structures of withanolides. (A) Withaferin A falls under the family of naturally occurring C28- steroidal lactones known as withanolides. (B) Structure of withaferin A.
Figure 2
Figure 2
Interactions of docked withaferin A with HSV POL before MD. (A) H-Bond interactions of the docked ligand with the polymerase residues. (B) Docked withaferin A forming van der waals interactions with the hydrophobic residues of HSV POL.
Figure 3
Figure 3
Interactions of docked withaferin A with HSV POL post-MD. (A) H-Bond interactions of the docked ligand with the polymerase residues. (B) Docked withaferin A forming van der waals interactions with the hydrophobic residues of HSV POL.
Figure 4
Figure 4
(A) Plot of B-factor values of HSV POL (red) and WA/HSV POL (blue). (B) Plot of root mean square deviation (RMSD) of Cα of HSV POL (protein) and WA/HSV POL (complex). (C) Plot of total energy of HSV POL (protein) and WA/HSV POL (complex).
Figure 5
Figure 5
Comparative analysis of pre- and post-MD simulated structures. (A) Ligplot of pre-MD structure (B) Ligplot of post-MD structure (C) Structural alignment of the ligand WA present in both structures. WA slides down to acquire a more structurally stable configuration by anchoring its tail inside the gorge of HSV POL.

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