School of Chemistry, The University of New South Wales, Sydney, NSW, 2052, Australia.
J Comput Aided Mol Des. 2023 Apr;37(4):167-182. doi: 10.1007/s10822-023-00499-0. Epub 2023 Mar 17.
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 (R = 0.77). The use of the recently enhanced Autodock Vina and zinc optimised AD4 force field also predicted ligand binding affinities with moderately strong correlation (R = 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.
碳酸酐酶是治疗许多疾病的有吸引力的药物靶点。本文研究了终态 MM/GBSA 方法在基于结合亲和力对碳酸酐酶抑制剂进行排序的能力。使用不同的原子电荷方案（Mulliken、ESP 和 NPA）和不同理论水平（包括 Hartree-Fock、B3LYP-D3(BJ) 和 M06-2X 与 6-31G(d,p)基组）评估了 MM/GBSA 结合能。对于 32 种不同抑制剂的大型测试集，B3LYP-D3(BJ)ESP 原子电荷的使用与实验结果具有最强的相关性（R=0.77）。最近增强的 Autodock Vina 和锌优化的 AD4 力场的使用也以较低的计算成本预测了与实验结果中等强度的相关性（R=0.64）。然而，对接的构象与晶体结构有很大的差异。总的来说，这项研究证明了对接在估计各种碳酸酐酶抑制剂的配体结合亲和力方面的适用性，并表明更理论上稳健的 MM/GBSA 模拟显示出提高预测结合亲和力准确性的潜力，只要使用经过验证的参数集。
