Rationally Designed NNRTI Agents

合理设计的 NNRTI 代理

• 批准号: 6549785
• 负责人: TARACAD VENKATACHALAM
• 金额: $ 10万
• 依托单位: PARADIGM PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549785
• 关键词: X ray crystallography; antiAIDS agent; antiviral agents; binding sites; chemical binding; chemical models; drug design /synthesis /production; human immunodeficiency virus 1; reverse transcriptase inhibitors; thiourea

DESCRIPTION (provided by applicant): We designed several reverse transcriptase inhibitors (RT) using our novel model of the non-nucleoside inhibitor binding pocket of HIV RT which combines high resolution crystal structure information from 9 NNRTI-RT complexes. We hypothesize that our binding pocket model can be used to design potent NNRTI inhibitors of RT and to predict how well they will bind to RT. Our SPECIFIC AIM 1 is to design and synthesize phenethylthiazolylthiourea derivatives containing alkoxy-substituted phenyl groups or halo-substituted phenyl groups for the inhibition of HIV reverse transcriptase. Under SPECIFIC AIM 2, we will evaluate the in vitro anti-HIV activity of novel phenethyl-thiazolylthiourea derivatives. Under SPECIFIC AIM 3, we will attempt to improve the composite binding pocket model of RT based on RT inhibition data obtained from compounds designed using the composite model. The successful completion of the proposed studies may provide the foundation for an effective salvage treatment program for multidrug resistant AIDS patients.

描述（由申请人提供）：我们使用HIV RT的非核苷抑制剂结合口袋的新模型设计了几种逆转录酶抑制剂（RT），该模型结合了来自9种NNRTI-RT复合物的高分辨率晶体结构信息。我们假设，我们的结合口袋模型可用于设计有效的NNRTI抑制剂RT和预测如何以及他们将结合RT。我们的具体目标1是设计和合成苯乙基噻唑基硫脲衍生物含有烷氧基取代的苯基或卤素取代的苯基抑制HIV逆转录酶。在特定目的2下，我们将评估新型苯乙基噻唑基硫脲衍生物的体外抗HIV活性。在特定目的3下，我们将尝试基于从使用复合模型设计的化合物获得的RT抑制数据来改进RT的复合结合口袋模型。这些研究的成功完成可能为多药耐药艾滋病患者的有效挽救治疗方案提供基础。