High-throughput Computational Docking Screen for Small-molecule Inhibitors of HIV

HIV小分子抑制剂的高通量计算对接筛选

• 批准号: 8012678
• 负责人: Simon Cocklin
• 金额: $ 23.11万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012678
• 关键词: Affinity; Anti-HIV Agents; Anti-HIV Therapy; Anti-Retroviral Agents; Antiviral Agents; Binding; Binding Sites; Biochemical; Biological Assay; Biological Process; Biology; Cell membrane; Complementary DNA; Computer software; Development; Docking; Drug resistance; Drug toxicity; Eligibility Determination; Event; Gagging; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV-1; Hand; Infection; Knowledge; Lead; Life Cycle Stages; Location; Mediating; Membrane; Membrane Microdomains; Molecular; Molecular Models; Monitor; Moscow; Mutagenesis; Nuclear Import; Nuclear Magnetic Resonance; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Physics; Process; Property; Proteins; RNA-Directed DNA Polymerase; Reagent; Regimen; Research; Retroviridae; Role; Russia; Screening procedure; Specificity; Staging; Structural Protein; Structure; Surface Plasmon Resonance; Viral; Virion; Virus; base; combat; design; inhibitor/antagonist; insight; matrix protein, Human immunodeficiency virus type 1; molecular modeling; novel; public health relevance; quantum; small molecule; stoichiometry; success; virtual

DESCRIPTION (provided by applicant): Despite recent progress in anti-HIV therapy, drug toxicity and the emergence of drug-resistant isolates during long-term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel antiviral agents. The HIV-1 matrix protein (MA) is a structural protein involved in several stages in the life cycle of the retrovirus. Although MA has long been known to be crucial for virion assembly, details regarding this function, and the domains responsible for mediating it, are still emerging. MA has also been implicated in nuclear import of HIV-1 cDNA and has recently been implicated in novel roles during infection including viral entry/uncoating, cytoskeletal-mediated transport, and targeting viral assembly to lipid rafts. The importance of MA in HIV-1 infection and its potential as an antiviral target have been demonstrated by the success of two strategies designed to block its function, one intrabody-based and another, more recent approach using small molecules. Given the success of these studies and the breadth of functions of HIV-1 MA, we have used a high-throughput computational docking (HTCD) approach to identify small molecules that may potentially bind to and disrupt the functions of HIV-1 MA. From this HTCD screen, we have identified 19 small molecules that are predicted to bind to HIV-1 MA in a structurally and functionally important region. From these 19 compounds, we have determined that eight possess antiviral activity. Importantly, the compounds that display antiviral activity can be grouped into three classes: early-stage inhibitors, late-stage inhibitors, and two compounds that appear to disrupt both early and late events. To our knowledge, these compounds represent the first small-molecule inhibitors that can disrupt both early- and late-stage processes in the replication cycle of HIV-1. In this proposal, we wish to establish the MA-targeted compounds that are suitable for further optimization via medicinal chemistry by investigating their binding affinity, stoichiometry, and binding site on MA (Specific Aim 1) in addition to determining their range, specificity, and mechanism of action (Specific Aim 2). We believe that execution of this cross-disciplinary strategy will successfully identify pharmacologically useful reagents that can be used to gain insight into the biological functions of HIV-1 MA protein, especially its role(s) in the early, pre-integration stage of the HIV-1 life cycle. Moreover, small molecules identified from this study hold promise as lead compounds for a new class of antiviral agent. PUBLIC HEALTH RELEVANCE: Despite the success of antiretroviral drug regimens, new targets for inhibition of HIV-1 replication are highly desirable, and new drugs are needed to combat the rising problem of drug resistance. The studies proposed in this application will characterize a class of compounds targeted at the HIV-1 matrix (MA) protein and that act via a novel mechanism at multiple stages in the HIV-1 life cycle. The compounds identified within this proposal have the potential to serve as templates for novel anti-HIV agents while also providing reagents with which to dissect the basic biology of HIV-1.

描述（由申请人提供）：尽管最近在抗艾滋病毒治疗方面取得了进展，但在艾滋病毒感染患者的长期治疗过程中，药物毒性和耐药分离株的出现要求寻找可用于开发新型抗病毒药物的新靶点。HIV-1基质蛋白（MA）是一种结构蛋白，参与逆转录病毒生命周期的几个阶段。尽管人们早就知道MA对病毒粒子组装至关重要，但关于这一功能的细节，以及负责介导它的结构域，仍在不断出现。MA还与HIV-1 cDNA的核输入有关，最近还与感染过程中的新角色有关，包括病毒进入/剥膜，细胞骨架介导的运输，以及靶向病毒组装到脂筏上。MA在HIV-1感染中的重要性及其作为抗病毒靶点的潜力已经被两种策略的成功证明，一种是基于体内的，另一种是最近使用小分子的方法。鉴于这些研究的成功和HIV-1 MA功能的广度，我们使用了高通量计算对接（HTCD）方法来识别可能与HIV-1 MA结合并破坏其功能的小分子。从这个HTCD筛选中，我们已经确定了19个小分子，预计将在结构和功能重要的区域与HIV-1 MA结合。从这19种化合物中，我们确定了8种具有抗病毒活性。重要的是，显示抗病毒活性的化合物可以分为三类：早期抑制剂，晚期抑制剂和两种似乎同时破坏早期和晚期事件的化合物。据我们所知，这些化合物代表了第一个可以破坏HIV-1复制周期早期和晚期过程的小分子抑制剂。在本提案中，我们希望通过研究其与MA的结合亲和力、化学计量学和结合位点（Specific Aim 1）来建立适合通过药物化学进一步优化的MA靶向化合物，并确定其范围、特异性和作用机制（Specific Aim 2）。我们相信，这一跨学科策略的执行将成功地确定药理学上有用的试剂，这些试剂可用于深入了解HIV-1 MA蛋白的生物学功能，特别是其在HIV-1生命周期的早期、前整合阶段的作用。此外，从这项研究中鉴定出的小分子有望成为一类新型抗病毒药物的先导化合物。