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

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.