Thermodynamics of binding of Zn2+ to carbonic anhydrase inhibitors

The Becke3LYP functional of DFT theory and the two-layered ONIOM (B3LYP/6–311 + G(d,p): MNDO) method were used to characterize 46 gas-phase complexes of 34 neutral and anionic ligands (H₂O, CH₃OH, CH₃COOH, CH₃CONH₂, HOSO₂NH₂, CO₂, HSO₂NH₂, CH₃SO₂NH₂, CH₃C(= O)NHOH, imidazole, NH₂SO₂NH₂, anions of 4-aminobenzenesulphonamide, saccharin, 1I9L, brinzolamide, dorzolamide, acetazolamide, further HO^(?), CH₃CO^(?), CH₃COO^(?), CH₃CONH^(?), N = N = N^(?), S = C = N^(?), CH₃C(= O)NHO^(?), HOCOO^(?), imidazoleN^(?), phenol-O^(?), HOSO₂NH^(?), ^(?)OSO₂NH^(?), ^(?)OSO₂NH₂, H₂NSO₂NH^(?), HSO₂NH^(?), CH₃SO₂NH^(?), and CF₃SO₂NH^(?), respectively) with Zn²⁺. Proton dissociation enthalpies and Gibbs energies of acidic inhibitors in the presence of zinc were computed. Their gas-phase acidity considerably increases upon chelation. Of the bases investigated, the weakest zinc affinity is exhibited by carbon dioxide (- 313.5 kJ mol^?1). Deprotonated inhibitors have higher affinities for zinc than the neutral ones. Compared to the other mono-deprotonated ligands the acetohydroxamic acid anion has the highest affinity for zinc (- 1872.7 kJ mol^?1). The zinc affinity of the acetazolamide anion computed using the hybrid ONIOM (B3LYP/6-311 + G(d,p): MNDO) method is in very good agreement with the full DFT ones and this method can be adopted to model large complexes of inhibitors with the active site of carbonic anhydrase.