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

使用自由能计算机计算方法改进 HIV 1 RT 抑制剂

• 批准号: 6119154
• 负责人: MATS ERIKSSON
• 金额: $ 0.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6119154
• 关键词: AIDS; biological products; biomedical resource; computers; immunology; infection; inflammation; lymphatic system; sexually transmitted diseases; virus

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.

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，差不多 已完成，是 HIV-1 RT TIBO 抑制剂的细化过程 开发更有效的药物来抑制疾病的进展 艾滋病毒感染。 这个过程涉及到新的方法 估计相对自由能的不同精度水平 一系列抑制剂的结合。 由于大量实验数据 可用于 TIBO 抑制剂，它们也适用于 计算方法的评估。 一般细化 方案是建议对先导抑制剂进行修改并对 修饰抑制剂的结合自由能。 最后， 最准确的方法 - “完整”自由能计算 - 是 对排名最高的修饰抑制剂进行研究，以揭示是否 建议的修改确实改善了抑制剂的结合。 这 该项目第二部分的目标是获得更深入的 了解耐药性的结构和动态原因 使用分子动力学（MD）模拟和免费的突变 能量扰动。 最初，我们将把这项研究的重点放在 HIV-1 RT 中的 Tyr181Cys 突变，因为该突变具有显着的 对两种衍生物 8 Cl- 和 9 的耐受性差异 Cl-TIBO。 我们的目的是从不同的角度研究这种差异 与蛋白质的接触，不同的补偿接触 突变 RT，以及可能的熵效应，例如 抑制剂或蛋白质迁移率。 然后自由能扰动将 确认不同游离态的耐药性差异 结合两种抑制剂的能量。 从这些见解中，我们可以 还获得有关如何设计抑制剂的想法，该抑制剂对于 野生型 HIV-1 RT 以及 Tyr181Cys 突变形式。 这 研究严重依赖计算机图形设施 由计算机图形实验室提供。 连续图形 检查模拟期间和期间的结构变化 扰动对于做出正确的决定至关重要 继续模拟/扰动。