Carbonic anhydrase is an attractive drug target for the treatment of many diseases. This paper examines the ability of end-state MM/GBSA methods to rank inhibitors of carbonic anhydrase in terms of their binding affinities. The MM/GBSA binding energies were evaluated using different atomic charge schemes (Mulliken, ESP and NPA) at different levels of theories, including Hartree–Fock, B3LYP-D3(BJ), and M06-2X with the 6–31G(d,p) basis set. For a large test set of 32 diverse inhibitors, the use of B3LYP-D3(BJ) ESP atomic charges yielded the strongest correlation with experiment (R² = 0.77). The use of the recently enhanced Autodock Vina and zinc optimised AD4_Zn force field also predicted ligand binding affinities with moderately strong correlation (R² = 0.64) at significantly lower computational cost. However, the docked poses deviate significantly from crystal structures. Overall, this study demonstrates the applicability of docking to estimate ligand binding affinities for a diverse range of CA inhibitors, and indicates that more theoretically robust MM/GBSA simulations show promise for improving the accuracy of predicted binding affinities, as long as a validated set of parameters is used.

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中文翻译：

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MM/GBSA 预测碳酸酐酶抑制剂的相对结合亲和力：原子电荷的影响以及与 Autodock4Zn 的比较

碳酸酐酶是治疗许多疾病的有吸引力的药物靶标。本文检验了最终状态 MM/GBSA 方法根据结合亲和力对碳酸酐酶抑制剂进行排序的能力。MM/GBSA 结合能在不同的理论水平上使用不同的原子电荷方案（Mulliken、ESP 和 NPA）进行评估，包括 Hartree–Fock、B3LYP-D3(BJ) 和 M06-2X 以及 6–31G(d, p) 基组。对于包含 32 种不同抑制剂的大型测试集，使用 B3LYP-D3(BJ) ESP 原子电荷与实验产生了最强的相关性 (R ²  = 0.77)。_{最近增强的 Autodock Vina 和锌优化的 AD4 Zn}力场的使用也预测了具有中等强相关性的配体结合亲和力（R ² = 0.64)，计算成本显着降低。然而，对接的姿势与晶体结构有很大的不同。总的来说，这项研究证明了对接在估计配体对多种 CA 抑制剂的结合亲和力方面的适用性，并表明理论上更稳健的 MM/GBSA 模拟有望提高预测结合亲和力的准确性，只要一组经过验证的使用参数。

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