The consequences of translational and rotational entropy lost by small molecules on binding to proteins
The consequences of translational and rotational entropy lost by small molecules on binding to proteins
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DOI：
10.1023/a:1022446720849
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发表时间：
2002-10-01
影响因子：
3.5
通讯作者：
Verdonk, ML
中科院分区：
文献类型：
--
作者：
Murray, CW;Verdonk, ML
当一个小分子与蛋白质结合时，它会损失大量的刚体平移和旋转熵。相关能垒的估计在文献中差异很大，但准确的估计在解释基于片段的药物发现技术的结果时很重要。本文描述了一种分析，该分析允许从已知亲和力和已知结合模式的两个片段连接在一起时产生的结合亲和力的增加来估计刚体熵势垒。本文回顾了相对较少的例子，其中有高质量的数据可用。从这些数据的分析，我们估计，由于刚体熵的损失，结合的障碍是15-20 kJ/mol，即在298 K时亲和的3个数量级。这种巨大的屏障解释了为什么在酶中很少观察到多个片段结合到不重叠的相邻位点。这种屏障也符合药物化学的经验，即配体关键结合区域的微小变化通常是酶难以耐受的。
When a small molecule binds to a protein, it loses a significant amount of rigid body translational and rotational entropy. Estimates of the associated energy barrier vary widely in the literature yet accurate estimates are important in the interpretation of results from fragment-based drug discovery techniques. This paper describes an analysis that allows the estimation of the rigid body entropy barrier from the increase in binding affinities that results when two fragments of known affinity and known binding mode are joined together. The paper reviews the relatively rare number of examples where good quality data is available. From the analysis of this data, we estimate that the barrier to binding, due to the loss of rigid-body entropy, is 15-20 kJ/mol, i.e. around 3 orders of magnitude in affinity at 298 K. This large barrier explains why it is comparatively rare to observe multiple fragments binding to non-overlapping adjacent sites in enzymes. The barrier is also consistent with medicinal chemistry experience where small changes in the critical binding regions of ligands are often poorly tolerated by enzymes.