A general and fast scoring function for protein-ligand interactions: A simplified potential approach
A general and fast scoring function for protein-ligand interactions: A simplified potential approach
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DOI：
10.1021/jm980536j
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发表时间：
1999-03-11
影响因子：
7.3
通讯作者：
Martin, YC
中科院分区：
文献类型：
--
作者：
Muegge, I;Martin, YC
提出了一种快速、简化的基于势的方法，该方法基于给定的蛋白质-配体复合体的三维结构来估计蛋白质-配体结合亲和力。这种基于知识的通用方法利用了从布鲁克海文蛋白质数据库中提取的已知蛋白质-配体复合体的结构信息，并将其转换为与距离相关的蛋白质-配体原子对的亥姆霍兹自由相互作用能(平均力势能，PMF)。研究发现，适当参考态的定义和考虑配位体体积的修正项的引入对于推导隐含地处理溶剂化和熵贡献的相关相互作用势是至关重要的。对于不同的蛋白质-配体复合体和结合到同一靶标的不同配体的集合，实验结合亲和力和计算得分之间存在显著相关性。对于布鲁克海文蛋白质数据库中的77个蛋白质-配体复合体，计算的分数与观察到的结合亲和力的标准偏差为1.8logK-I单位，R-2值为0.61。16个丝氨酸蛋白酶复合体的标准差为1.0logK-I单位，R-2值为0.86，结果最佳。一组33个抑制剂模拟HIV-1蛋白酶的晶体结构，与测量的抑制常数的标准偏差为0.8logK-I单位，R-2值为0.74。与显示与观察到的结合亲和力相似或有时更好相关性的经验得分函数相比，我们的方法不涉及推导适合给定训练集的蛋白质-配体复合体的观察到的结合亲和力的特定参数。我们比较了八个不同蛋白质-配体复合体测试集的PMF分数、Bohm‘s分数(Ludi)和烟雾分数的表现。研究发现，对于大多数测试集，PMF分数表现最好。这里提出的新方法的优点在于它的普遍性，因为推导原子相互作用势不需要关于测量的结合亲和力的知识。概述了新的评分函数在对接研究中的使用。
A fast, simplified potential-based approach is presented that estimates the protein-ligand binding affinity based on the given 3D structure of a protein-ligand complex. This general, knowledge-based approach exploits structural information of known protein-ligand complexes extracted from the Brookhaven Protein Data Bank and converts it into distance-dependent Helmholtz free interaction energies of protein-ligand atom pairs (potentials of mean force, PMF). The definition of an appropriate reference state and the introduction of a correction term accounting for the volume taken by the ligand were found to be crucial for deriving the relevant interaction potentials that treat solvation and entropic contributions implicitly. A significant correlation between experimental binding affinities and computed score was found for sets of diverse protein-ligand complexes and for sets of different ligands bound to the same target. For 77 protein-ligand complexes taken from the Brookhaven Protein Data Bank, the calculated score showed a standard deviation from observed binding affinities of 1.8 log K-i units and an R-2 value of 0.61. The best results were obtained for the subset of 16 serine protease complexes with a standard deviation of 1.0 log K-i unit and an R-2 value of 0.86. A set of 33 inhibitors modeled into a crystal structure of HIV-1 protease yielded a standard deviation of 0.8 log K-i units from measured inhibition constants and an R-2 value of 0.74. In contrast to empirical scoring functions that show similar or sometimes better correlation with observed binding affinities, our method does not involve deriving specific parameters that fit the observed binding affinities of protein-ligand complexes of a given training set. We compared the performance of the PMF score, Bohm's score (LUDI), and the SMOG score for eight different test sets of protein-ligand complexes. It was found that for the majority of test sets the PMF score performs best. The strength of the new approach presented here lies in its generality as no knowledge about measured binding affinities is needed to derive atomic interaction potentials. The use of the new scoring function in docking studies is outlined.