Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Vermont Campus, 261 Mountain View Drive, Colchester, Vermont 05446, USA.
J Med Chem. 2012 Mar 8;55(5):2035-47. doi: 10.1021/jm201217q. Epub 2012 Feb 17.
Treatment of ionization and tautomerism of ligands and receptors is one of the unresolved issues in structure-based prediction of binding affinities. Our solution utilizes the thermodynamic master equation, expressing the experimentally observed association constant as the sum of products, each valid for a specific ligand-receptor species pair, consisting of the association microconstant and the fractions of the involved ligand and receptor species. The microconstants are characterized by structure-based simulations, which are run for individual species pairs. Here we incorporated the multispecies approach into the QM/MM linear response method and used it for structural correlation of published inhibition data on mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2) by 66 benzothiophene and pyrrolopyridine analogues, forming up to five tautomers and seven ionization species under experimental conditions. Extensive cross-validation showed that the resulting models were stable and predictive. Inclusion of all tautomers and ionization ligand species was essential: the explained variance increased to 90% from 66% for the single-species model.
配体和受体的离解和互变异构的处理是基于结构的结合亲和力预测中未解决的问题之一。我们的解决方案利用热力学主方程，将实验观察到的结合常数表示为乘积的和，每个乘积都适用于由特定的配体-受体物种对组成，包括结合微常数和参与的配体和受体物种的分数。微常数通过基于结构的模拟来表征，这些模拟是针对各个物种对进行的。在这里，我们将多物种方法纳入到 QM/MM 线性响应方法中，并将其用于结构相关的研究，研究了发表的关于丝裂原激活的蛋白激酶（MAPK）-激活蛋白激酶（MK2）被 66 苯并噻吩和吡咯并吡啶类似物抑制的数据，在实验条件下形成了多达五个互变异构体和七个离解物种。广泛的交叉验证表明，所得模型是稳定和可预测的。包含所有互变异构体和离解配体物种是至关重要的：从单物种模型的 66%增加到 90%，解释了方差。
