Expanding the druggable genome

描述 摘要： 许多参与蛋白质-蛋白质相互作用的蛋白质由于参与复合物形成的大而平的结合表面而被认为是不可药用的。此外，目前获得口服生物利用度和药物样性质的规则与药物这种具有挑战性的靶标通常所需的分子类型不一致。该提案概述了一项计划，以开发药物的蛋白质，目前被认为是“不可药用”的方法。“该策略将涉及快速消除蛋白质，这些蛋白质几乎没有机会从基于片段的筛选中被药物化，并开发更好的计算方法来实现这一目标。将开发优化的基于片段的方法、基于结构的设计和改进的计算工具，以进行引线识别和优化。为了获得具有良好口服生物利用度的分子，将挑战当前关于药物样的规则，并将系统地检查分子大小、柔性、极性表面积、电荷和其他参数的重要性。此外，将开发测定方法，以确定缺乏生物利用度的原因，以确定如何纠正这些缺陷。通过以系统的方式在多个测定中合成和测试化合物（包括对照化合物），将建立用于对具有挑战性的靶标进行药物化的指南和方法。这项研究可能会彻底改变我们的药物发现方法，导致新药在所有治疗领域更好地治疗疾病，从而对人类健康产生巨大影响。 公共卫生相关性： 在人类基因组中的30，000种蛋白质中，只有大约3，000种被认为是可通过小有机分子药物化的;然而，这些不可药物化的蛋白质中的许多是高度验证的，并且可以作为药物发现中的重要靶标，提供合适的方法来开发药物这些技术上具有挑战性的靶标。如该提案所述，扩大可药用基因组可能是一种有效的方法。

DESCRIPTION Abstract: Many proteins involved in protein-protein interactions are considered to be undruggable due to the large, flat binding surfaces involved in complex formation. Moreover, the current rules to obtain oral bioavailability and drug-like properties are not consistent with the type of molecules often needed to drug such challenging targets. This proposal outlines a plan to develop approaches for drugging proteins that are currently considered to be "undruggable." The strategy will involve quickly eliminating proteins with little chance of being druggable from fragment-based screens and developing better computational approaches to accomplish this goal. Optimized fragment-based methods, structure-based design, and improved computational tools will be developed for lead identification and optimization. To obtain molecules with good oral bioavailability, the current rules concerning druglikeness will be challenged, and the importance of molecular size, flexibility, polar surface area, charge, and other parameters will be examined systematically. In addition, assays will be developed to identify the reasons for the lack of bioavailability to determine how to correct these deficiencies. By synthesizing and testing compounds (including control compounds) in multiple assays in a systematic fashion, the guidelines and approaches for drugging challenging targets will be established. This research could revolutionize our approach to drug discovery, lead to new drugs to better treat disease in all therapeutic areas, and thus have a dramatic impact on human health. Public Health Relevance: Of the 30,000 proteins in the human genome, only about 3,000 are thought to be druggable by small organic molecules; however, many of these undruggable proteins are highly validated and could serve as important targets in drug discovery providing suitable approaches are developed to drug these technically challenging targets. Expanding the druggable genome as outlined in this proposal could a