Calculation of cyclodextrin binding affinities: Energy, entropy, and implications for drug design
Calculation of cyclodextrin binding affinities: Energy, entropy, and implications for drug design
复制标题
DOI：
10.1529/biophysj.104.049494
复制
发表时间：
2004-11-01
影响因子：
3.4
通讯作者：
Gilson, MK
中科院分区：
文献类型：
--
作者：
Chen, W;Chang, CE;Gilson, MK
第二代 Mining Minima 方法对于 α-、β- 和 γ-环糊精与苯、间苯二酚、氟比洛芬、萘普生和萘丁美酮的结合产生精确到 0.8 kcal/mol 以内的结合亲和力。这些计算需要在商用计算机上花费数小时甚至一天的时间。计算还表明，结合时构型熵的变化与缔合相反，变化幅度高达 24 kcal/mol，这主要是由于结合态与自由态的能量井变窄所致，而不是由于结合时不同低能构象数量的下降。此外，还发现给定环糊精-客体复合物的结合构象之间的构型熵有很大差异。这一结果表明，必须考虑构型熵，才能可靠地对宿主-客体和配体-蛋白质复合物中的对接构象进行排序。与熵-焓补偿的常见实验观察非常相似，计算出的熵变化显示出与平均势加溶剂化能的变化的近线性关系。
The second generation Mining Minima method yields binding affinities accurate to within 0.8 kcal/mol for the associations of alpha-, beta-, and gamma-cyclodextrin with benzene, resorcinol, flurbiprofen, naproxen, and nabumetone. These calculations require hours to a day on a commodity computer. The calculations also indicate that the changes in configurational entropy upon binding oppose association by as much as 24 kcal/mol and result primarily from a narrowing of energy wells in the bound versus the free state, rather than from a drop in the number of distinct low-energy conformations on binding. Also, the configurational entropy is found to vary substantially among the bound conformations of a given cyclodextrin-guest complex. This result suggests that the configurational entropy must be accounted for to reliably rank docked conformations in both host-guest and ligand-protein complexes. In close analogy with the common experimental observation of entropy-enthalpy compensation, the computed entropy changes show a near-linear relationship with the changes in mean potential plus solvation energy.