Institute of Molecular Recognition Chemistry, CNR, via Mario Bianco 9, 20131 Milano, Italy.
Pharmaceuticals (Basel). 2012 Sep 10;5(9):944-62. doi: 10.3390/ph5090944.
Proteins carry out their functions through interactions with different partners. Dynamic conformational switching among different structural sub-states favors the adaptation to the shapes of the different partners. Such conformational changes can be determined by diverse biochemical factors, such as ligand-binding. Atomic level investigations of the mechanisms that underlie functional dynamics may provide new opportunities for the discovery of leads that target disease-related proteins. In this review, we report our views and approaches on the development of novel and accurate physical-chemistry-based models for the characterization of the salient aspects of the ligand-regulated dynamics of Hsp90, and on the exploitation of such new knowledge for the rational discovery of inhibitors of the chaperone.
蛋白质通过与不同的伙伴相互作用来发挥其功能。不同结构亚基之间的动态构象转换有利于适应不同伙伴的形状。这种构象变化可以由多种生化因素决定，如配体结合。对功能动力学背后机制的原子水平研究可能为发现针对疾病相关蛋白质的先导化合物提供新的机会。在这篇综述中，我们报告了我们对开发新的、准确的基于物理化学的模型来描述 Hsp90 配体调节动力学的突出方面的看法和方法，以及利用这些新知识进行合理发现伴侣蛋白抑制剂的方法。
