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

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).