TO INVESTIGATE LONG-RANGE DYNAMIC EFFECTS FROM ANTIVIRAL COMPOUNDS BOUND IN THE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人鼻病毒(HRV)和柯萨奇病毒(CV)是微冠状病毒家族的两个成员：HRV是普通感冒的病原体，是一种研究广泛的药物靶标，其与抗病毒化合物和受体的复合体具有丰富的结构信息。小分子化合物在衣壳的5倍对称轴附近的内袋中与HRV病毒蛋白1(VP1)结合，并通过抑制脱壳过程来中断病毒的生命周期。我们认为这种抗病毒活性的分子机制涉及抗病毒化合物对构象动力学的长期影响。受体识别是病毒生命周期的另一个主要组成部分。HRV和CV似乎主要通过电荷互补识别受体，但Lys残基的突变结果不能从已知的晶体结构中解释。当抗病毒化合物占据VP1口袋时，残基在5倍轴上的构象波动减少，即使口袋不与这些残基直接接触。这些长程效应可能是这些化合物抗病毒活性的来源。这些影响将通过对HRV的五聚体单元和HRV与Win抗病毒化合物的复合体的MD模拟来探索。关于柯萨奇病毒A21(CVA21)的类似研究也在计划中。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human rhinovirus (HRV) and coxsackievirus (CV) are two members of the Picornaviridae family: HRV, a causative agent of the common cold, is a well studied pharmaceutical target with considerable structural information known about its complexes with antiviral compounds and receptor. Small molecule compounds bind to the HRV viral protein 1 (VP1) in an internal pocket located near the 5-fold symmetry axis of the capsid shell, and interrupt the virus life cycle by inhibiting the uncoating process. We propose the molecular mechanism for this antiviral activity involves long-range effects of antiviral compounds on conformational dynamics. Receptor recognition is another primary component of the virus life cycle. HRV and CV seem to recognize receptor largely by charge complementarity, but results from mutagenesis of a Lys residue cannot be explained from the known crystal structures. Conformational fluctuations of residues at the 5-fold axis are decreased when antiviral compounds occupy the VP1 pocket even though the pocket is not in direct contact with these residues. These long-range effects may be the origin of the antiviral activity of these compounds. The effects will be explored by MD simulations of the pentameric unit of HRV and complexes of HRV with WIN antiviral compounds. Similar studies on coxsackievirus A21 (CVA21) are also planned.