MD SIMULATIONS OF DESIGNED HIV INHIBITORS

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。 HIV-1蛋白酶是一种篮状病毒酶，参与 病毒的成熟。抑制该酶可降低感染者的病毒载量 个人。虽然目前有几种药物可以抑制细胞的功能 HIV蛋白酶，设计和开发新的、新的药物的需要势在必行，因为 蛋白水解酶继续快速变异为耐药形式。上世纪90年代初 弗里德曼和他的同事发表了两篇描述富勒烯和富勒烯的报告 作为HIV-1蛋白酶抑制剂的衍生物(荞球)，因为它们确实是正确的 大小和形状，以适应和抑制活性部位。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特性- 事实证明，基于bayball的游戏是一个不可逾越的挑战。最近我们有 发表了一项关于一类重要分子行为的计算研究 具有不同疏水/亲水性质的新型多面体分子。而当 研究这些分子，我们意识到它们的大小和形状非常相似 到C60，而它们的键的性质允许它们更易溶于水。 我们有兴趣进行一项可行性的计算调查 使用这些分子作为HIV-1蛋白酶抑制剂。此前，我们已经表演了 HIV蛋白酶的MD模拟没有任何配体；有C60；在络合中 使用我们的分子，使用MacroModel(系列)中实现的随机动力学 在OPLS2005/GBSA(水面)表面。我们想要使用一个 不同的力场和采样算法，所以我们一直在自学 正确使用琥珀和德斯蒙德模拟程序包。我们要求 300,000个单元，以便在多个处理器上运行琥珀和德斯蒙德 考试和学习的时间。

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.