A MULTISCALE APPROACH TO TARGET THE ACHILLES HEEL OF P53 CANCER MUTANTS

摘要 可以说，P53是人类最重要的肿瘤抑制蛋白之一。在近50%的 在所有人类癌症中，P53被发现是不起作用的，主要是由于单点突变。这个 这项建议的主要目标是详细了解最频繁的 P53癌基因突变对蛋白质结构和动力学的影响，并对一种新的 识别能够重新激活不稳定的P53的小分子的计算方法 癌症突变体-一种代表着一种很有前途的药物发现新方法。我们的目标是 为了扩大我们对截短和全长p53状态的结构动力学的理解- 最先进的分子动力学模拟，以发现具有 还没有被实验表征的。随后，我们计划使用这个新的结构 识别具有新作用机制的小分子并揭示新潜力的信息 以这种重要转录因子为靶点的治疗途径。

SUMMARY p53 is arguably one of the most important tumor suppressor proteins in humans. In almost 50% of all human cancers, p53 is found to be nonfunctional mostly due to single point mutations. The primary goals of this proposal are to gain a detailed understanding of the effect of most-frequent p53 cancer mutations on the protein structure and dynamics, and to leverage a novel computational methodology that identifies small molecules able to reactivate destabilized p53 cancer mutants—a method that represents a promising new approach to drug discovery. We aim to extend our understanding of the structural dynamics of truncated and full-length p53 with state- of-the-art molecular dynamics simulations in order to discovery novel druggable pockets that have not yet been experimentally characterized. Subsequently we plan to use this new structural information to identify small molecules with novel mechanisms of action and reveal new potential therapeutic avenues targeting this vital transcription factor.