MD SIMULATIONS OF DESIGNED HIV INHIBITORS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 HIV-1蛋白酶是一种篮状病毒酶，参与HIV-1的免疫反应。 病毒的成熟。抑制这种酶可以降低感染者体内的病毒载量。 个体虽然目前有几种药物可以抑制神经元的功能， 艾滋病毒蛋白酶，需要设计和开发新的，新颖的药物势在必行， 蛋白酶继续快速突变成耐药形式。上世纪90年代初 弗里德曼和他的同事发表了两份报告， 衍生物（巴基球）作为HIV-1蛋白酶的抑制剂，因为它们恰恰是正确的 大小和形状以适合并抑制活性位点。不幸的是，这项工作没有 导致可行的药物作为碳氢化合物的水溶性特征- 基于巴基球被证明是一个不可逾越的挑战。最近我们 发表了一项计算研究的分子行为的一个重要类别的 具有不同疏水/亲水特性的新型多面体分子。而 通过研究这些分子，我们发现它们的大小和形状 到C60，而它们的键的性质允许它们更易溶于水。 我们感兴趣的是进行计算的可行性调查， 使用这些分子作为HIV-1蛋白酶抑制剂。此前，我们已经执行 无任何配体的HIV蛋白酶的MD模拟;与C60;和络合 与我们的分子，使用随机动力学，在宏模型（串行）实现 在OPLS 2005/GBSA（水）表面上。我们想用一个 不同的力场和采样算法，所以我们一直在教自己 正确使用安珀和德斯蒙德模拟软件包我们要求 30，0000个单位，以便在多个处理器上运行AMBER和Desmond缩短 测试和学习时间。

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. The HIV-1 protease is a basket-shaped viral enzyme that participates in the maturation of the virus. Inhibition of this enzyme reduces the viral load in infected individuals. While several drugs are currently available that inhibit the function of the HIV protease, the need to design and develop new, novel drugs is imperative as the protease continues to rapidly mutate into drug-resistant forms. In the early 1990s Friedman and co-workers published two reports describing fullerene and fullerene derivatives (buckyballs) as inhibitors of HIV-1 protease as they are precisely the right size and shape to fit into and inhibit the active site. Unfortunately, this work did not lead to viable drugs as the aqueous solubility characteristics of the hydrocarbon- based buckyballs proved to be an insurmountable challenge. Recently we have published a computational study of the molecular behavior of an important class of new polyhedral molecules with different hydrophobic/hydrophilic properties. While studying these molecules we realized that their size and shape is quite comparable to C60 while the nature of their bonds allows them to be much more water soluble. We are interested in performing a computational investigation of the feasibility of using these molecules as HIV-1 protease inhibitors. Previously, we have performed MD simulations of the HIV protease sans any ligands; with C60; and in complexation with our molecules, using stochastic dynamics as implemented in MacroModel (serial) on the OPLS2005/GBSA(water) surface. We would like to verify our results using a different force field and sampling algorithm and so we have been teaching ourselves to properly use the AMBER and Desmond simulation packages. We are requesting 30,0000 units in order to run AMBER and Desmond on multiple processors shortening the testing and learning times.