MD SIMULATIONS OF DESIGNED HIV INHIBITORS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 HIV-1蛋白酶是一种篮状病毒酶，参与病毒的成熟。这种酶的抑制降低了感染个体的病毒载量。虽然目前有几种药物可以抑制HIV蛋白酶的功能，但由于蛋白酶继续快速突变成耐药形式，因此设计和开发新的新型药物的需求势在必行。在20世纪90年代初，弗里德曼和他的同事发表了两份报告，描述了富勒烯和富勒烯衍生物（巴基球）作为HIV-1蛋白酶的抑制剂，因为它们的大小和形状正好适合并抑制活性位点。不幸的是，这项工作并没有导致可行的药物，因为烃基巴基球的水溶性特征被证明是一个不可逾越的挑战。最近，我们发表了一个计算研究的分子行为的一类重要的新的多面体分子具有不同的疏水/亲水性能。在研究这些分子时，我们意识到它们的大小和形状与C60相当，而它们的键的性质使它们更具水溶性。我们有兴趣进行计算研究的可行性，使用这些分子作为HIV-1蛋白酶抑制剂。以前，我们已经进行了MD模拟的HIV蛋白酶无任何配体;与C60;并与我们的分子络合，使用随机动力学在宏模型（串行）上的OPLS 2005/GBSA（水）表面上实现。我们希望使用不同的力场和采样算法来验证我们的结果，因此我们一直在自学如何正确使用AMBER和Desmond仿真软件包。我们需要30，0000台，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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.