Abstract：
Whenever a protein fails to fold into its native structure, a profound detrimental effect is likely to occur, and a disease is often developed. Protein conformational disorders arise when proteins adopt abnormal conformations due to a pathological gene variant that turns into gain/loss of function or improper localization/degradation. Pharmacological chaperones are small molecules restoring the correct folding of a protein suitable for treating conformational diseases. Small molecules like these bind poorly folded proteins similarly to physiological chaperones, bridging non-covalent interactions (hydrogen bonds, electrostatic interactions, and van der Waals contacts) loosened or lost due to mutations. Pharmacological chaperone development involves, among other things, structural biology investigation of the target protein and its misfolding and refolding. Such research can take advantage of computational methods at many stages. Here, we present an up-to-date review of the computational structural biology tools and approaches regarding protein stability evaluation, binding pocket discovery and druggability, drug repurposing, and virtual ligand screening. The tools are presented as organized in an ideal workflow oriented at pharmacological chaperones\' rational design, also with the treatment of rare diseases in mind.
摘要：
每当蛋白质无法折叠成天然结构时，可能会产生深远的不利影响，并且经常会出现疾病。当蛋白质由于病理基因变体而采取异常构象时，就会出现蛋白质构象障碍，该病理基因变体转变为功能的获得/丧失或不正确的定位/降解。药理学伴侣是小分子,其恢复适于治疗构象疾病的蛋白质的正确折叠。像这样的小分子结合折叠不良的蛋白质，类似于生理伴侣，桥接非共价相互作用(氢键，静电相互作用，和范德华接触）由于突变而松动或丢失。药理伴侣的发展涉及，除其他外，靶蛋白及其错误折叠和重折叠的结构生物学研究。这样的研究可以在许多阶段利用计算方法。这里,我们介绍了有关蛋白质稳定性评估的计算结构生物学工具和方法的最新综述，结合口袋的发现和可药用性，药物再利用,和虚拟配体筛选。这些工具被呈现为以药理学伴侣“合理设计”为导向的理想工作流程，也与罕见疾病的治疗有关。
