促进抗病毒药物促进HBV衣壳自我组装的因素的鉴定

StephenW

J Chem Inf Model. 2018 Jan 8. doi: 10.1021/acs.jcim.7b00471. [Epub ahead of print]
Identification of Factors Promoting HBV Capsid Self-Assembly by Assembly-Promoting Antivirals.
Rath SL, Liu H, Okazaki S, Shinoda W.
Abstract

Around 270 million individuals currently live with Hepatitis B Virus (HBV) infection. Heteroaryldihydropyrimidines (HAPs) are a family of antivirals that target the HBV capsid protein and induce aberrant self-assembly. The capsids formed resemble the native capsid structure, but are unable to propagate the virus progeny due to lack of RNA/DNA. Under normal conditions, self-assembly is initiated by the viral genome. The mode of action of HAPs, however, remains largely unknown. Here, using molecular dynamics simulations, we attempted to understand HAP action by comparing the dynamics of capsid proteins with and without HAPs. We found that the inhibitor is more stable in higher oligomers. It retains its stability in hexamer throughout 1 μs of our simulation. Our results also show that the inhibitor might help in stabilizing the C-terminus, the HBc 149-183 arginine rich domain of the capsid protein. The C-termini of dimers interact with each other, assisted by the HAP inhibitor. During capsid assembly, the termini are supposed to directly interact with the viral genome, thereby suggesting that the viral genome might work in a similar way to stabilize the capsid protein. Our results may help in understanding the underlying molecular mechanism of HBV capsid self-assembly, which should be crucial for exploring new drug targets and structure-based drug design.

PMID:
    29309148
DOI:
    10.1021/acs.jcim.7b00471

StephenW

J Chem Inf模型。 2018年1月8日。doi：10.1021 / acs.jcim.7b00471。 [电子版提前打印]
促进抗病毒药物促进HBV衣壳自我组装的因素的鉴定。
Rath SL，Liu H，Okazaki S，Shinoda W.
抽象

目前约有2.7亿人患有乙型肝炎病毒（HBV）感染。杂芳基二氢嘧啶（HAPs）是靶向HBV衣壳蛋白并诱导异常自组装的抗病毒剂家族。形成的衣壳类似天然衣壳结构，但由于缺乏RNA / DNA而不能繁殖病毒后代。在正常情况下，自组装是由病毒基因组启动的。然而，HAPs的行动方式在很大程度上还不清楚。在这里，使用分子动力学模拟，我们试图通过比较具有和不具有HAP的衣壳蛋白的动力学来理解HAP行为。我们发现抑制剂在更高级的低聚物中更稳定。它在整个1μs的仿真中保持其在六聚体中的稳定性。我们的结果还表明，抑制剂可能有助于稳定C端，即衣壳蛋白的HBc149-183富含精氨酸的结构域。二聚体的C-末端相互作用，由HAP抑制剂协助。在衣壳装配期间，末端应该直接与病毒基因组相互作用，从而表明病毒基因组可能以相似的方式起作用以稳定衣壳蛋白。我们的研究结果可能有助于理解HBV衣壳自组装的基本分子机制，这对于探索新的药物靶点和基于结构的药物设计应该是至关重要的。

结论：
    29309148
DOI：
    10.1021 / acs.jcim.7b00471