Quantum Chemical Prediction of the Acidities of Sulfonamide Inhibitors of Carbonic Anhydrase.

Abstract

This study examined two pKa calculation approaches (direct and proton exchange schemes) that employ high-level quantum chemical methods and implicit solvent models to predict aqueous Brønsted acidities of a large set of sulfonamides. For gas-phase deprotonation energies, the DSD-PBEP86-D3(BJ) double-hybrid functional provided the best agreement with the LNO-CCSD(T)/CBS benchmark with a mean absolute deviation less than 2 kJ mol-1 when the aug-cc-pVTZ or larger basis sets are used. For a large test set of 54 primary and secondary sulfonamides, the use of the DSD-PBEP86-D3(BJ)/aug-cc-pVTZ level of theory in conjunction with SM12 solvation free energies predict their pKa values with a mean accuracy of 0.9 units. In comparison, the SMD and ADF-COSMO-RS models have slightly higher mean errors of 1.4 and 1.1 pKa units provided that the proton exchange scheme was employed to cancel the systematic errors in these models. The performance of these protocols was less ideal when applied to sulfonic acids, sulfamates, and N-substituted sulfonamides, indicating that the degree of error cancellation is sensitive to the chemical environment around the -NH2 head group. The validated protocols were then used to estimate the pKa values of arylsulfonamide carbonic anhydrase inhibitors, which are used to correct their experimentally measured binding free energies to account for deprotonation of the sulfonamide group upon binding to the enzyme. These corrected values did not have a significant impact on the correlation with MMGBSA binding free energies obtained from classical MD simulations where the ligand is usually considered in the deprotonated form.