Computational Design of Inhibitor Specificity

描述（由申请人提供）：开发治疗快速发展的病毒感染的新方法是一个重要的研究领域。该项目将寻求开发药物治疗的一般方法，这些方法可导致在艾滋病情况下避免耐药性的抑制剂，但广泛适用于传染病和癌症。我们将继续发展和改进底物包膜假说，将开发和应用小分子配体的逆计算设计方法，将研究底物包膜假说的失败来改进方法，并将通过与有机和药物化学、酶分析、蛋白质晶体学和病毒学。因为基本上所有针对传染病和癌症开发的治疗方法都受到耐药变异选择的限制，因此通常适用的避免或至少延迟耐药的策略将对药物开发产生巨大影响。该项目将理解和改进已被充分研究的HIV-1蛋白酶的底物包膜和相关方法，但所开发的方法将广泛适用于基于靶标的传染病和癌症耐药。底物包膜假说认为，存在于底物共享体积内的抑制剂不太容易受到抗性突变的影响，因为这些突变体仍然必须处理底物。初步的工作已经证明了底物包膜假说的一些成功和局限性，拟议的项目将在HIV-1蛋白酶的背景下进一步测试和发展底物包膜假说。基材包络假设的延伸包括除了占据共同基材体积的几何标准之外的其他基材样模式。我们以前的工作包括底物包络假设的成功和失败。失败的是我们设计的分子，当合成时完全结合在底物包膜内，但不能牢固地结合在一组耐药变体上。通过研究这些与野生型和耐药变体结合的分子和底物，我们将寻求对底物包膜假说失败的机制理解，这将用于开发底物包膜假说的改进版本。最后，深度测序技术的进步使得考虑绘制候选靶点的功能突变空间成为可能，并利用功能突变空间作为开发不受抗性突变影响的抑制剂的指导。该项目将开发和研究使用功能突变空间作为设计避免抗性抑制剂的基础的方法。我们将比较这种方法与底物包膜方法的成功，注意到新方法适用于目标，无论它们是否是酶，而底物包膜假设的当前状态仅适用于酶。

DESCRIPTION (provided by applicant): The development of new approaches to treat rapidly evolving viral infections is an important area of research. This project will pursue general methods for the development of drug therapies that lead to inhibitors that avoid resistance in the context of AIDS, yet broadly applicable to infectious disease and cancer. We will continue to develop and improve the substrate envelope hypothesis, will develop and apply inverse computational design methods for small-molecule ligands, will study failures of the substrate envelope hypothesis to improve the approach, and will develop alternative approaches related to the substrate envelope hypothesis in the context of HIV-1 protease through a collaborative effort with experimental groups expert in organic and medicinal chemistry, enzyme assays, protein crystallography, and virology. Because essentially all therapies developed for infectious disease and cancer are limited by the selection of resistant variants, strategies for avoiding or a least delaying resistance that are generally applicable would have tremendous impact on drug development. This project will understand and improve the substrate envelope and related approaches in the well studied HIV-1 protease, but the methods developed will be broadly applicable to target-based infectious disease and cancer drug resistance. The substrate envelope hypothesis maintains that inhibitors that reside within the volume shared by substrates are less susceptible to resistance mutations, because such mutants must still process substrates. Preliminary work has demonstrated some success and shown some limitations of the substrate envelope hypothesis, and the proposed project will further test and develop the substrate envelope hypothesis in the context of HIV-1 protease. Extensions of the substrate envelope hypothesis include other modes of being substrate-like besides the geometric criteria of occupying the common substrate volume. Our previous work includes successes and failures of the substrate envelope hypothesis. The failures are molecules we designed that when synthesized bind wholly within the substrate envelope but fail to bind robustly across a panel of drug-resistant variants. By studying these molecules and substrates bound to wild type and drug-resistant variants, we will seek a mechanistic understanding of failures of the substrate envelope hypothesis, which will use to develop improved versions of the substrate envelope hypothesis. Finally, advances in deep sequencing technology make it possible to consider mapping the functional mutational space of candidate targets, and using the functional mutational space as a guide to the development of inhibitors that are not susceptible to resistance mutations. This project will develop and study methodology for using the functional mutational space as a basis for the design of inhibitors that avoid resistance. We will compare the success of this approach to the substrate envelope approach, noting that the new approach is applicable to targets whether they are enzymes or not, whereas the current state of the substrate envelope hypothesis is applicable to enzymes only.