Arylsulfonamides as inhibitors for carbonic anhydrase: prediction & validation

Abstract

Arylsulfonamide derivatives are widely studied high affinity inhibitors of the isozyme human carbonic anhydrase II (hCA II). From molecular dynamics simulations and MM-GBSA calculations, reliable (R = 0.89) relative binding free energies are determined for 17 previously experimentally characterized protein–ligand complexes. Decomposition of these energies led to the identification of critical amino acid residues with a significant contribution to the affinity towards the ligands. In particular, Leu198 was predicted as a key residue and was subjected to computational mutagenesis. This prediction was verified experimentally by producing hCA II mutants L198A, L198F and L198Q and determining the resulting affinities towards inhibitor 1. The computed vs. experimental energies are in good agreement thus suggesting that the force field parameters reported herein are useful for the in silico design of a wider range of carbonic anhydrase inhibitors.