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

该项目涉及HIV-1的非核苷类TiBO系列 逆转录酶(RT)抑制剂。第一部分，几乎 完成，是HIV-1 RT Tibo抑制剂的精炼过程 开发更有效的药物来抑制肿瘤的进展 艾滋病毒感染。这一过程涉及新的方法，这些方法 估算相对自由能的不同精度水平 一系列抑制剂的结合。由于许多实验数据是 可用于TIBO抑制剂，它们也适用于 对计算方法的评价。总体上的提炼 方案是建议修改铅抑制剂并对 根据其结合自由能来修饰抑制剂。最后， 最准确的方法--“全”自由能计算--是 对排名最高的修饰抑制剂进行检测，以揭示 建议的修饰确实改善了抑制剂的结合。这个 项目第二部分的目标是获得更深层次的 对耐药的结构性和动力性原因的认识 使用分子动力学(MD)模拟和FREE的突变 能量微扰。首先，我们将把这项研究的重点放在 HIV-1RT中的Tyr181Cys突变，因为该突变具有显著的 对两种衍生物8Cl-和9的抵抗力差异 CL-Tibo。我们的目标是从不同的角度来研究这种差异 与蛋白质接触，不同的补偿接触 突变RT，以及可能的熵效应，例如 抑制物或蛋白质的迁移率。自由能微扰将会 从不同的游离态确认抗药性的差异 结合这两种抑制剂的能量。从这些见解来看，我们可能会 还可以获得如何设计抑制剂的想法，这是一种有效的 野生型HIV-1RT以及Tyr181Cys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。一个连续的图形 在模拟期间和期间检查结构变化 对于如何做出正确的决策，扰动是必不可少的 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.