The majority of drug-like molecules contain at least one ionizable group, and many common drug scaffolds are subject to tautomeric equilibria. Thus, these compounds are found in a mixture of protonation and/or tautomeric states at physiological pH. Intrinsically, standard classical molecular dynamics (MD) simulations cannot describe such equilibria between states, which negatively impacts the prediction of key molecular properties in silico. Following the formalism described by de Oliveira and co-workers (J. Chem. Theory Comput. 2019, 15, 424–435) to consider the influence of all states on the binding process based on alchemical free-energy calculations, we demonstrate in this work that the multistate method replica-exchange enveloping distribution sampling (RE-EDS) is well suited to describe molecules with multiple protonation and/or tautomeric states in a single simulation. We apply our methodology to a series of eight inhibitors of factor Xa with two protonation states and a series of eight inhibitors of glycogen synthase kinase 3β (GSK3β) with two tautomeric states. In particular, we show that given a sufficient phase-space overlap between the states, RE-EDS is computationally more efficient than standard pairwise free-energy methods.

中文翻译：

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有效解释炼金术自由能计算中互变异构和质子化的多态方法


大多数药物样分子含有至少一个可电离基团，并且许多常见的药物支架都存在互变异构平衡。因此，这些化合物在生理pH下以质子化和/或互变异构状态的混合物存在。从本质上讲，标准经典分子动力学 (MD) 模拟无法描述状态之间的这种平衡，这会对计算机中关键分子特性的预测产生负面影响。遵循 de Oliveira 及其同事描述的形式主义 (J. Chem. Theory Comput. 2019, 15, 424–435)，基于炼金术自由能计算来考虑所有状态对结合过程的影响，我们在此证明研究表明，多态方法复制交换包络分布采样（RE-EDS）非常适合在单次模拟中描述具有多个质子化和/或互变异构态的分子。我们将我们的方法应用于一系列八种具有两种质子化状态的 Xa 因子抑制剂和一系列八种具有两种互变异构状态的糖原合酶激酶 3β (GSK3β) 抑制剂。特别是，我们表明，给定状态之间足够的相空间重叠，RE-EDS 在计算上比标准成对自由能方法更有效。