Free energy calculations: Use and limitations in predicting ligand binding affinities
Free energy calculations: Use and limitations in predicting ligand binding affinities
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DOI：
10.1002/9780470125939.ch4
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发表时间：
2000-01-01
期刊：
影响因子：
--
通讯作者：
Agarwal, A
中科院分区：
文献类型：
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作者：
Reddy, MR;Erion, MD;Agarwal, A
在20世纪80年代初，蛋白质晶体学的进步和计算机能力的巨大进步表明，药物发现研究正处于一个新时代的边缘，在这个时代，通过使用蛋白质结构和计算机模拟复杂的生物过程，药物将以前所未有的效率和速度被识别。经过近20年的研究和只有少量的成功，2现在很明显，进入这个时代的药物设计将需要更多的时间和进一步提高的准确性，用于预测分子相互作用能的计算。基于结构的药物设计未能显著影响药物发现时间表主要归因于现有方法无法准确和快速。1计算结果的不准确性归因于多种因素。在某些情况下，起始蛋白质结构不正确地反映了结合相互作用。这可能是因为低质量的结构数据，构象空间的计算采样不足，或配体结合，导致意外的蛋白质构象变化。
In the early 1980s, advances in protein crystallography and substantial gains in computer power suggested that drug discovery research was on the verge of a new age, l an age in which drugs would be identified with unprecedented efficiency and speed through the use of protein structure and computer simulations of complex biological processes. After nearly two decades of research and only a small number of successes, 2 it is now clear that entry into this era of drug design will require more time and further improvements in the accuracy of the calculations used for predicting molecular interaction energies. The failure of structure-based drug design to significantly impact drug discovery timelines is attributed primarily to the inability of the available methodologies to be accurate and rapid. 1 Inaccuracies in the computed results are attributed to multiple factors. In some cases, the starting protein structure improperly reflects the binding interactions. This may be because of low quality structural data, inadequate computational sampling of conformational space, or ligand binding that results in unexpected protein conformational changes.