Molecular docking, MM/GBSA, FEP/MD, and DFT/MM MD studies on predicting binding affinity of carbonic anhydrase II inhibitors

Abstract

Human carbonic anhydrase II (hCAII) is one of the zinc-containing metalloenzymes that catalyzes various hydration reactions. We report an investigation of whether modern computational tools can predict inhibitory potency of a set of sulfonamides against hCAII. The methods used are molecular docking, molecular dynamics simulations coupled with the free energy perturbation theory (FEP/MD), molecular mechanics combined with the generalized Born and surface area continuum solvation (MM/GBSA), and quantum mechanics/molecular mechanics (QM/MM) metadynamics simulations. A comparison is presented between experimental and computed binding free energy properties. All MD-based approaches demonstrate robust performance with R² values in the range of 0.89 to 0.99 for the subset of structurally simple sulfonamides, underscoring the importance of accounting for dynamic protein–ligand interactions. With regard to the other subset comprised of structurally more diverse sulfonamides, for which the QM(B3LYP)/MM(CHARMM) metadynamics approach is less affordable, the FEP/MD method yields an R² value of 0.70. Notably, the R² value increases to 0.80 after the removal of one outlier (chlorzolamide).