Hydrophobicity in HIV-1 Protease Inhibition: QSAR Study

HIV-1 蛋白酶抑制中的疏水性：QSAR 研究

• 批准号: 7005718
• 负责人: Rajni Garg
• 金额: $ 11.85万
• 依托单位: CLARKSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7005718
• 关键词: AIDS; antiAIDS agent; aspartic endopeptidases; chemical models; chemical structure function; computer simulation; drug design /synthesis /production; enzyme activity; human immunodeficiency virus 1; hydropathy; model design /development; molecular dynamics; protease inhibitor

DESCRIPTION (provided by applicant): Acquired Immunodeficiency Syndrome (AIDS) and its related disorders, caused by retrovirus Human Immunodeficiency Virus Type 1 (HIV-1), are a major health concern worldwide. HIV-1 Protease (HIVPR) is one of the major viral targets for the development of new chemotherapeutics. Currently, many HIVPR inhibitor drugs are used in combination with HIV-1 Reverse Transcriptase (HIVRT) inhibitor drugs. However, the use of current drugs regimens has several shortcomings, such as adherence, tolerability, long-term toxicity and drug- and cross-resistance. HIV-1 is also known to have several mutants. Therefore, the development of new HIVPR inhibitors that are less toxic, more tolerable, convenient and active against drug resistant viruses is highly desirable. To expedite the search for a more potent and less toxic anti-HIVPR inhibitor, we propose to continue detailed Quantitative Structure-Activity Relationship (QSAR) study on these inhibitors. We will expand this study to perform Comparative QSAR analyses for the lateral validation of the developed QSAR models. This study will cover enzyme inhibitory and antiviral activity of various structurally diverse classes of HIVPR inhibitors, for wild-type as well as mutant HIVPR. The observations of comparative QSAR will be supported by molecular modeling. Because the presence of a hydrophobic channel at the binding site of HIVPR is well established, emphasis will be on studying the role of hydrophobicity of the substituent of the ligands in the design of more effective HIVPR inhibitor. These studies will enhance our understanding of hydrophobic interactions of structurally diverse classes of HIVPR inhibitors, and establish Comparative QSAR as a novel approach in the design and development of HIVPR inhibitors.

描述（由申请人提供）：由逆转录病毒人类免疫缺陷病毒 1 型 (HIV-1) 引起的获得性免疫缺陷综合症 (AIDS) 及其相关疾病是全世界的主要健康问题。 HIV-1 蛋白酶 (HIVPR) 是开发新化疗药物的主要病毒靶标之一。目前，许多HIVPR抑制剂药物与HIV-1逆转录酶(HIVRT)抑制剂药物联合使用。然而，当前药物治疗方案的使用存在一些缺点，例如依从性、耐受性、长期毒性以及药物耐药性和交叉耐药性。 HIV-1 还已知有多种突变体。因此，开发毒性较小、耐受性更强、使用方便且对耐药病毒具有活性的新型HIVPR抑制剂是非常必要的。为了加快寻找更有效、毒性更小的抗 HIVPR 抑制剂，我们建议继续对这些抑制剂进行详细的定量构效关系 (QSAR) 研究。我们将扩展这项研究，以进行比较 QSAR 分析，以对开发的 QSAR 模型进行横向验证。这项研究将涵盖各种结构不同类别的 HIVPR 抑制剂的酶抑制和抗病毒活性，适用于野生型和突变型 HIVPR。比较 QSAR 的观察结果将得到分子模型的支持。由于 HIVPR 结合位点疏水通道的存在已得到充分证实，因此重点将放在研究配体取代基疏水性在设计更有效的 HIVPR 抑制剂中的作用。这些研究将增强我们对结构不同类别的 HIVPR 抑制剂的疏水相互作用的理解，并将比较 QSAR 确立为设计和开发 HIVPR 抑制剂的新方法。