Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
BMC Bioinformatics. 2011;12 Suppl 13(Suppl 13):S22. doi: 10.1186/1471-2105-12-S13-S22. Epub 2011 Nov 30.
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.
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.
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.
单纯疱疹病毒 1 和 2 可引起人类多种感染，包括唇疱疹和脑炎。以前针对疱疹病毒的抗病毒研究主要集中在开发核苷类似物上，这些类似物可以抑制病毒聚合酶并终止复制的病毒 DNA。然而，这些药物具有内在的非特异性，因为它们除了可以抑制病毒聚合酶外，还可以抑制细胞聚合酶。本研究试图阐明天然 Withaferin A 抑制病毒 DNA 聚合酶的作用机制，从而为其作为新型抗疱疹药物的开发提供证据。
发现 Withaferin A 与之前报道的 4-氧代-DHQ 抑制剂非常相似。观察到 Withaferin A 与残基 Gln617、Gln618、Asn815 和 Tyr818 结合，所有这些残基对聚合酶的正常功能都至关重要。对接和分子动力学模拟获得的构象比较表明，结合构象发生了很大变化。这些结果表明，对接后观察到的初始受体-配体相互作用可能由于受体刚性对接算法而受到限制，并且模拟运行后观察到的构象和相互作用在能量上更有利。
我们进行了对接和分子动力学模拟研究，以阐明潜在草药药物 Withaferin A 与单纯疱疹病毒 DNA 聚合酶结构的结合机制。我们的对接模拟结果表明配体与受体具有高结合亲和力。进行了长达 10 ns 的新从头 MD 模拟，使我们能够评估所研究系统的动态行为，并证实对接结果，以及确定酶-抑制剂相互作用中的关键残基。目前的 MD 模拟支持这样的假设，即 Withaferin A 是一种潜在的配体，可靶向/抑制单纯疱疹病毒的 DNA 聚合酶。这些研究的结果也将指导设计具有高特异性和高效活性的 DNA POL 选择性抑制剂，以加强针对单纯疱疹病毒这一危险生物战剂的现有治疗手段。
