Computational Design of Fusion Inhibitors Targeting Drug-resistant HIVgp41

针对耐药 HIVgp41 的融合抑制剂的计算设计

• 批准号: 8467315
• 负责人: ROBERT C. RIZZO
• 金额: $ 29.57万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467315
• 关键词: Accounting; Affinity; Award; Binding; Biological Assay; Cell fusion; Cells; Chemicals; Complement; Complex; Computer Assisted; Crystallography; Custom; Development; Docking; Drug Design; Drug Targeting; Drug resistance; Eligibility Determination; Event; Fuzeon; Goals; Growth; HIV; Laboratories; Lead; Letters; Libraries; Life; Life Cycle Stages; Ligand Binding; Literature; Maps; Membrane Fusion; Methods; Modeling; Molecular; Outcome; Pattern; Peptides; Pharmaceutical Preparations; Positioning Attribute; Procedures; Proteins; Public Health; Publishing; Research; Resistance profile; Side; Site; Staging; Structural Models; Structure; Synthesis Chemistry; Testing; Therapeutic; Time; Validation; Viral; Viral Proteins; Virus Inhibitors; Virus Replication; Work; analog; base; cytotoxicity; design; experience; improved; inhibitor/antagonist; innovation; molecular dynamics; novel; pharmacophore; programs; public health relevance; resistance mutation; scaffold; screening; small molecule; virtual

DESCRIPTION (provided by applicant): The long-term goal of our research is to develop critically-needed small molecule drugs to help treat the approximately 33 million people worldwide living with HIV. The emergence of deleterious drug-resistance mutations against currently-approved therapies necessitates new strategies for targeting HIV life-cycle events that include complementary inhibition mechanisms and exploitation of regions with high sequence conservation. An innovative approach, recently developed in our lab, aims to leverage the wealth of energetic and structural information inherent to atomic-level molecular footprints - interaction maps occurring within targetable pockets on viral proteins - to rationally identify, develop, and design novel small molecule inhibitors against the viral protein gp41. As outlined below, we have strong evidence suggesting that footprints derived from regions on gp41 encode information regarding which residues are most critical for ligand binding and that our development of a novel computational means to harness this information is a potentially ground-breaking way to screen for, or alternatively, design-from-scratch small molecule fusion inhibitors. Here, the objectives are to utilize the power of footprints to rationally design small molecules that specifically bind to gp41 and inhibit membrane fusion. Our published atomic models for peptide inhibitors (C34 and T20/Fuzeon) with gp41 will enable us to target the known hydrophobic pocket in addition to other regions that, until now, have yet to be exploited. Our central hypothesis is that small organic molecules which make interactions with gp41, in an energetically similar manner as key side-chains on known peptide inhibitors, will make effective leads for therapeutics. Furthermore, by including footprints derived from interactions occurring within conserved gp41 regions during the identification and development stages, we postulate compounds will be more likely to have robust resistance profiles. This hypothesis is based on several observations, including our identification of seven experimentally-verified inhibitors usin a new virtual screening protocol tailored to account for footprint-based similarity. We have also used footprints in conjunction with molecular dynamics simulations to explain the origins of T20 drug resistance as well as show that association of C-helix peptide inhibitors can be driven solely by changes within the conserved gp41 pocket, supporting the premise that the conserved pocket region is an important drug target site. Promising preliminary results, in which we have integrated footprints with computational de novo design methods, facilitates, for the first time, custom construction from scratch of small molecules which make specific footprint patterns with gp41 in a similar way as a known reference. In Aim #1 we will custom-design small molecule inhibitors specifically tailored to energetically favorable interfaces on gp41. In Aim #2 we will develop experimentally verified gp41 leads to have improved gp41 activity. In Aim #3 we will identify other targetable events in the gp41 pre-hairpin model.

描述（由申请人提供）：我们研究的长期目标是开发急需的小分子药物，以帮助治疗全球约 3300 万艾滋病毒感染者。针对目前批准的疗法的有害耐药突变的出现，需要针对艾滋病毒生命周期事件的新策略，包括补充抑制机制和利用具有高度序列保守性的区域。我们实验室最近开发的一种创新方法，旨在利用原子级分子足迹（病毒蛋白的目标口袋内发生的相互作用图）固有的丰富能量和结构信息，合理地识别、开发和设计针对病毒蛋白 gp41 的新型小分子抑制剂。如下所述，我们有强有力的证据表明，来自 gp41 区域的足迹编码了哪些残基对配体结合最关键的信息，并且我们开发了一种新的计算方法来利用这些信息，这可能是筛选或从头开始设计小分子融合抑制剂的潜在突破性方法。在这里，我们的目标是利用足迹的力量来合理设计特异性结合 gp41 并抑制膜融合的小分子。我们发布的带有 gp41 的肽抑制剂（C34 和 T20/Fuzeon）原子模型将使我们能够靶向已知的疏水口袋以及迄今为止尚未开发的其他区域。我们的中心假设是，与 gp41 相互作用的有机小分子，其能量方式与已知肽抑制剂的关键侧链相似，将为治疗提供有效的先导。此外，通过包括在识别和开发阶段保守 gp41 区域内发生的相互作用产生的足迹，我们假设化合物将更有可能具有强大的耐药性。这一假设基于多项观察结果，包括我们使用一种新的虚拟筛选方案鉴定了七种经过实验验证的抑制剂，该方案专为考虑基于足迹的相似性而定制。我们还使用足迹与分子动力学模拟相结合来解释 T20 耐药性的起源，并表明 C 螺旋肽抑制剂的关联可以仅由保守的 gp41 口袋内的变化驱动，支持保守的口袋区域是重要的药物靶位点的前提。我们将足迹与计算从头设计方法集成在一起，这是有希望的初步结果，首次促进了从头开始定制小分子的构建，这些小分子以与已知参考类似的方式用 gp41 形成特定的足迹图案。在目标#1中，我们将定制设计小分子抑制剂，专门针对 gp41 上的能量有利界面。在目标 #2 中，我们将开发经过实验验证的 gp41 线索，以提高 gp41 活性。在目标 #3 中，我们将识别 gp41 发夹前模型中的其他可目标事件。