Rational, Computational Design of Novel anti-AIDS Drugs

新型抗艾滋病药物的合理计算设计

• 批准号: 6653698
• 负责人: RICHARD H SMITH
• 金额: $ 13.45万
• 依托单位: MCDANIEL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653698
• 关键词: RNA directed DNA polymerase; antiAIDS agent; drug design /synthesis /production; drug resistance; drug screening /evaluation; enzyme structure; mathematical model; method development; nucleoside inhibitor; protein binding; protein structure function

DESCRIPTION (provided by applicant): This proposal seeks to address the problem of drug resistance to nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) through the refinement and extension of our computational methodology for predicting drug activity prior to synthesis and clinical testing. The goal is to build upon our past accomplishments in the use of Monte Carlo (MC) simulations coupled with a linear response (LR) method to predict activity against variant forms of RT (Y181C, Y188C, L1001, V106A, K101 E, K103N, and possible double mutants) that are resistant to all current anti-AIDS drugs. Hybrid quantum mechanics/molecular mechanics (QM/MM) refinements to the MC methodology and routines for protein backbone approximation will be incorporated to improve the accuracy of predictions. A new, rapid preliminary screening technique employing a combinatorial computational approach will be used to evaluate candidate structures prior to full computational evaluation. The proposed changes in methodology are anticipated to significantly improve the treatment of both the inhibitor and the protein backbone, problems of paramount importance if computational methods are to succeed in accurately predicting host-guest interactions in novel systems. The overall goal is to enhance the speed and accuracy of designing effective inhibitors of resistant forms of RT. The new methodology will be employed in the design of new members of a novel class of NNRTI's, BPBrs, developed in conjunction with collaborators at NCI-Frederick. Newly proposed BPBI analogs showing good predicted activity against variant forms of RT will be synthesized and tested for broad spectrum activity. While a specific and extremely important objective of the proposal is to discover new inhibitors targeted toward NNIRT resistant viruses found in AIDS patients, the general computational methodology developed herein has broad applications to the accurate description of binding in all host-guest interactions that involve proteins and organic molecules.

描述（由申请人提供）： 该提案旨在解决HIV-1逆转录酶非核苷抑制剂（NNRTIs）的耐药性问题，通过改进和扩展我们的计算方法来预测药物活性之前的合成和临床试验。我们的目标是建立在我们过去的成就，使用蒙特卡罗（MC）模拟加上线性响应（LR）方法来预测对所有当前抗艾滋病药物具有抗性的RT变体形式（Y181 C，Y188 C，L1001，V106 A，K101 E，K103 N和可能的双突变体）的活性。混合量子力学/分子力学（QM/MM）的改进MC方法和蛋白质骨架近似的例程将被纳入，以提高预测的准确性。一种新的，快速的初步筛选技术采用组合计算方法将被用来评估候选结构之前，充分的计算评估。预计拟议的方法学变化将显著改善抑制剂和蛋白质骨架的治疗，如果计算方法要成功地准确预测新型系统中的主客体相互作用，这些问题至关重要。总体目标是提高设计RT耐药形式有效抑制剂的速度和准确性。新方法将用于设计与NCI-Frederick的合作者联合开发的新型NNRTI BPBr的新成员。将合成新提出的对RT的变体形式显示出良好的预测活性的BPBI类似物，并测试其广谱活性。虽然该提案的一个具体且极其重要的目标是发现针对艾滋病患者中发现的NNIRT抗性病毒的新抑制剂，但本文开发的一般计算方法在涉及蛋白质和有机分子的所有主客体相互作用中的结合的准确描述中具有广泛的应用。

项目成果

HIV-1 reverse transcriptase variants: molecular modeling of Y181C, V106A, L100I, and K103N mutations with nonnucleoside inhibitors using Monte Carlo simulations in combination with a linear response method.

HIV-1 逆转录酶变体：使用蒙特卡罗模拟结合线性响应方法，使用非核苷抑制剂对 Y181C、V106A、L100I 和 K103N 突变进行分子建模。

• DOI: 10.3109/10559610390484203
• 发表时间: 2003
• 期刊: Drug design and discovery
• 作者: Smith,MarilynBKroeger;Ruby,Sandra;Horouzhenko,Stanislav;Buckingham,Bryan;Richardson,Julia;Puleri,Ina;Potts,Emily;Jorgensen,WilliamL;Arnold,Edward;Zhang,Wanyi;Hughes,StephenH;Michejda,ChristopherJ;SmithJr,RichardH
• 通讯作者: SmithJr,RichardH