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被认为是不可药物的，因为参与复杂形成的大而平的结合表面。此外，目前获得口服生物利用度和类药物特性的规则与通常需要给这些具有挑战性的靶点药物的分子类型不一致。这项提案概述了一项计划，即开发一种方法来给目前被认为是“无法下药”的蛋白质下药。该战略将包括从基于片段的筛查中快速消除几乎不可能被下药的蛋白质，并开发更好的计算方法来实现这一目标。将开发优化的基于碎片的方法、基于结构的设计和改进的计算工具，以识别和优化铅。为了获得具有良好口服生物利用度的分子，目前关于类药物的规则将受到挑战，分子大小、灵活性、极性表面积、电荷和其他参数的重要性将被系统地检查。此外，将开发分析以确定缺乏生物利用度的原因，以确定如何纠正这些不足。通过系统地在多个测试中合成和测试化合物(包括对照化合物)，将建立对具有挑战性的目标进行药物治疗的指导方针和方法。这项研究可能会彻底改变我们的药物发现方法，导致在所有治疗领域更好地治疗疾病的新药，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种被认为可以被有机小分子下药；然而，这些无法下药的蛋白质中的许多都得到了高度验证，如果开发出合适的方法来对这些具有技术挑战性的靶点进行药物治疗，它们可能会成为药物发现的重要靶点。扩大这项提案中概述的可用药基因组可能会

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