REFINEMENT OF HIV 1 RT INHIBITORS USING FREE ENERGY COMPUTER CALCULATION METHODS

该项目涉及HIV-1的非核苷TIBO系列 逆转录酶（RT）抑制剂。 第一部分，几乎 完成，是一个HIV-1 RT TIBO抑制剂的精制过程， 开发更有效的药物， 艾滋病毒感染。 这个过程涉及新的方法， 用于估计相对自由能的不同精度水平 一系列抑制剂的结合。 由于大量的实验数据 可用于TIBO抑制剂，它们也适用于 计算方法的评价。 一般细化 方案是建议修改铅抑制剂和排名 修饰的抑制剂在其结合自由能方面。 最后， 最精确的方法-“完全”自由能计算-是 对排名最高的改性抑制剂进行研究，以揭示 所建议的修饰确实改善了抑制剂结合。 的 该项目第二部分的目标是获得更深入的 了解耐药的结构和动力学原因 突变与使用分子动力学（MD）模拟和免费 能量扰动 首先，我们将把这项研究集中在 HIV-1 RT中的Tyr 181 Cys突变，因为该突变具有显著的 对两种衍生物8 Cl-和9的抗性差异 C. TIBO 我们的目的是研究这种差异， 与蛋白质的接触，不同的补偿接触， 突变体RT，以及可能的熵效应，例如 抑制剂或蛋白质迁移率。 自由能扰动将 证实了在不同的自由基方面的耐药性差异 结合两种抑制剂的能量。 从这些见解中，我们可以 我还想知道如何设计一种抑制剂， 野生型HIV-1 RT以及Tyr 181 Cys突变形式。 这 研究在很大程度上依赖于计算机图形设备 由计算机图形实验室提供。 连续图形 在模拟过程中以及在 扰动是必不可少的，以作出正确的决定， 继续模拟/扰动。

This project concerns the non-nucleoside TIBO series of HIV-1 reverse transcriptase (RT) inhibitors. The first part, almost completed, is a refinement process of HIV-1 RT TIBO inhibitors in the development of more efficient drugs which inhibit the progression of HIV infection. This process involves novel methods that work on different levels of accuracy for estimating the relative free energy of binding of a series of inhibitors. Since much experimental data is available for the TIBO inhibitors, they are also suitable for an evaluation of the computational methods. The general refinement scheme is to suggest modifications of lead inhibitors and rank the modified inhibitors in terms of their binding free energy. Finally, the most accurate method - "full" free energy calculations - is performed on the highest ranked modified inhibitors to reveal whether the suggested modification really improved the inhibitor binding. The goal of the second part of the project is to gain a deeper understanding of structural and dynamic reasons for drug resistant mutations with the use of molecular dynamics (MD) simulations and free energy perturbations. Initially, we will focus this study on the Tyr181Cys mutation in HIV-1 RT since this mutation has a marked difference in resistance towards the two derivatives 8 Cl- and 9 Cl-TIBO. Our aim is to study this difference in terms of different contacts with the protein, different compensating contacts in the mutant RT, and possible entropic effects, such as differences in inhibitor or protein mobilities. Free energy perturbations will then confirm the differences in drug resistance in terms of different free energy of binding the two inhibitors. From these insights, we might also get ideas on how to design an inhibitor, which is a potent for wild type HIV-1 RT as well as for the Tyr181Cys mutated form. This research is heavily dependent on the computer graphics facilities provided by the Computer Graphics Laboratory. A continuous graphical inspection of structural changes during the simulations and during the perturbations is essential to make correct decisions on how to continue the simulations/perturbations.