Endpoint methods using continuum‐solvent models are widely used to estimate protein–ligand affinity. A recently developed method, MM/3D‐RISM, estimates the solvation energy using statistical mechanics by 3D‐RISM. This method is theoretically expected to accurately describe solvation effects and to also be less dependent on protein–ligand systems. In this study, we examined the performance of MM/3D‐RISM for a set of α‐thrombin inhibitors with a non‐congeneric series of ligands, containing three diverse chemical scaffolds. The standard MM/3D‐RISM showed a weak correlation (R² = 0.191) but correctly estimated affinity for two of the three scaffolds. However, the simplest inhibitor, benzamidine, was not ranked appropriately. From visual inspection of inhibitor‐binding modes, an attempt was made to incorporate the direct interaction between a ligand and water molecules into MM/3D‐RISM. A model (Model‐1) dealing with directly interacting water molecules (Wat) as an independent component of a protein (R)–ligand (L) complex‐formation, that is, R + L + Wat → R–L–Wat, showed a better linearity (R² = 0.422) than that of the standard MM/3D‐RISM model and achieved a good ranking of all three scaffolds of α‐thrombin inhibitors. Additionally, an attempt was made to model avidin–biotin system with a congeneric series of inhibitors, and results showed that both the standard MM/3D‐RISM model (R² = 0.839) and Model‐1 (R² = 0.695) satisfactorily estimated the affinity.

中文翻译：

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试图将配体与水分子之间直接相互作用的效应纳入MM / 3D-RISM

使用连续溶剂模型的端点方法被广泛用于估计蛋白质-配体亲和力。最近开发的方法MM / 3D-RISM使用3D-RISM的统计机制估计溶剂化能。从理论上讲，该方法有望准确描述溶剂化作用，并且对蛋白质-配体系统的依赖性也较小。在这项研究中，我们检查了MM / 3D-RISM对一组具有非同类配体的α-凝血酶抑制剂的性能，该配体包含三种不同的化学支架。标准MM / 3D‐RISM的相关性较弱（R ² = 0.191），但正确估计了对三个支架中两个的亲和力。但是，最简单的抑制剂苯甲am并没有得到适当的排名。通过目视检查抑制剂结合模式，尝试将配体和水分子之间的直接相互作用纳入MM / 3D-RISM。一个模型（Model-1）将直接相互作用的水分子（Wat）作为蛋白质（R）-配体（L）复合物形成的独立成分，即R + L + Wat→R–L–Wat，表现出更好的线性度（R ² = 0.422），比标准的MM / 3D-RISM模型高，并且在所有三个α-凝血酶抑制剂支架上均取得了良好的排名。此外，尝试使用同类抑制剂系列对抗生物素蛋白-生物素系统进行建模，结果表明标准MM / 3D-RISM模型（R ²  = 0.839）和Model-1（R ²  = 0.695）均令人满意亲和力。