MM/GBSA prediction of relative binding affinities of carbonic anhydrase inhibitors: effect of atomic charges and comparison with Autodock4(Zn)

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(2) = 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 (R(2) = 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. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10822-023-00499-0.