Advanced Integrated Molecular Simulations Based Prediction of Sulfonamide Natural Compound Binding to Cytosolic Carbonic Anhydrase Enzymes

Abstract This study explores the intricate interactions between sulfonamide natural compounds and the human cytosolic carbonic anhydrase (CA) isoform. hCA‐II, the most commonly targeted physiological isoform for inhibiting glaucoma owing to its distribution in the cellular region of the eye. Here, we extensively analyzed natural compounds for their specific interaction with hCA‐II, emphasizing the nature of their molecular associations and potential implications in biological processes. Over half a million natural compounds were filtered from two databases based on their structure‐activity relationship (SAR) with 4‐hydroxy‐3‐nitro‐5‐({[4‐(trifluoromethyl)phenyl]carbamoyl}amino)benzene‐1‐sulfonamide (J3 V) and 628 SAR scaffolds were identified. Those molecules went through different toxicity checks and forty leads were discovered. All lead molecules were docked to the hCA‐II active site among them thirty‐two molecules showed better docking scores. The top hits compounds with higher drug‐likeness, including J3V were explored further. MD simulation studies revealed that all four leads displayed comparable stability to the J3V with hCA‐II for 200 ns. Umbrella sampling revealed that S32 had a lower ΔG (−57.88 kJ/mol) than J3V (−54.86 kJ/mol), indicating stronger binding. These results suggest undiscovered sulfonamide natural compounds, particularly S32, exhibit superior binding affinity and stability compared to J3V, potentially offering effective hCA‐II inhibition for glaucoma management.