Computational Design of Fusion Inhibitors Targeting Drug-resistant HIVgp41

描述(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3300万艾滋病毒携带者。针对目前批准的治疗方法出现有害的耐药性突变，需要针对艾滋病毒生命周期事件的新战略，其中包括互补的抑制机制和开发具有高度序列保守性的区域。我们实验室最近开发了一种创新的方法，旨在利用原子级分子足迹固有的丰富的能量和结构信息-发生在病毒蛋白质上的靶向口袋内的相互作用图-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区域的足迹编码了关于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手段来利用这些信息，这可能是筛选或从头开始设计小分子融合抑制剂的一种开创性方法。在这里，目标是利用足迹的力量来合理设计与gp41特异性结合并抑制膜融合的小分子。我们发表的带有gp41的多肽抑制剂(C34和T20/Fuzeon)的原子模型将使我们能够瞄准已知的疏水口袋，以及到目前为止尚未开发的其他区域。我们的中心假设是，与gp41相互作用的小有机分子，在能量上类似于已知肽抑制剂上的关键侧链，将成为治疗的有效先导。此外，通过包括在鉴定和发育阶段保守的gp41区域内发生的相互作用所产生的足迹，我们假设化合物将更有可能具有强大的抗性图谱。这一假设是基于几个观察结果，包括我们使用一种新的虚拟筛选方案识别了七种经过实验验证的抑制剂，该方案是为考虑基于足迹的相似性而定制的。我们还使用足迹结合分子动力学模拟来解释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点的假设。有希望的初步结果，其中我们将足迹与计算从头设计方法相结合，首次促进了从零开始定制小分子的构建，这些小分子以与已知参考相似的方式与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上能量有利的界面量身定做。在目标2中，我们将开发经过实验验证的gp41先导，以提高gp41的活性。在目标#3中，我们将确定gp41前发夹模型中的其他目标事件。

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.