VALIDATE: A new method for the receptor-based prediction of binding affinities of novel ligands
VALIDATE: A new method for the receptor-based prediction of binding affinities of novel ligands
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DOI：
10.1021/ja9539002
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发表时间：
1996-04-24
影响因子：
15
通讯作者：
Marshall, GR
中科院分区：
文献类型：
--
作者：
Head, RD;Smythe, ML;Marshall, GR
VALIDATE是一种预测新配体与已知三维结构的受体结合亲和力的混合方法。该方法计算配体和受体-配体复合体的物理化学性质，以估计结合自由能。结合能用分子力学计算，结合能用互补疏水表面积等性质通过启发式方法估算结合能。组装了51个晶体配合物的不同训练集，并计算了它们的相关物理化学性质。通过偏最小二乘(PLS)统计或神经网络分析(SONNIC)对这些性质进行分析，以生成用于一般预测配体与已知三维结构的受体的亲和力的模型。通过三个独立的测试集验证了该模型能够预测未包括在训练集中的新的复合体的亲和力：14个已知三维结构的复合体，包括3个DNA复合体，一类不包括在训练集中的化合物，13个适合于HIV-1蛋白酶的HIV蛋白酶抑制剂，以及11个适合于热裂解酶的热裂解蛋白抑制剂。
VALIDATE is a hybrid approach to predict the binding affinity of novel ligands for receptors of known three-dimensional structure. This approach calculates physicochemical properties of the ligand and the receptor-ligand complex to estimate the free energy of binding. The enthalpy of binding is calculated by molecular mechanics while properties such as complementary hydrophobic surface area are used to estimate the entropy of binding through heuristics. A diverse training set of 51 crystalline complexes was assembled, and their relevant physicochemical properties were computed. These properties were analyzed by partial least squares (PLS) statistics, or neural network analysis (SONNIC), to generate models for the general prediction of the affinity of ligands with receptors of known three-dimensional structure. The ability of the model to predict the affinity of novel complexes not included in the training set was demonstrated with three independent test sets: 14 complexes of known three-dimensional structure including 3 DNA complexes, a class of compound not included in the training set, 13 HIV protease inhibitors fit to HIV-1 protease, and 11 thermolysin inhibitors fit to thermolysin.