Exploring Natural Product Primary Sulfamates as Carbonic Anhydrase II Ligands: A Computational Approach

Abstract

Carbonic anhydrase II (CA II) is a validated metalloenzyme target, classically inhibited by primary sulfonamides such as acetazolamide (AZM), but issues with selectivity and physicochemical properties drive the search for alternative zinc-binding scaffolds. Here, seven naturally occurring primary sulfamates and sulfonamides—(−)-altemicidin, psammaplin C, nucleocidin, 5′-O-sulfamoyladenosine, 5′-O-sulfamoyl-2-chloroadenosine, 5′-O-sulfamoyl-2-bromoadenosine, and 5′-O-sulfamoyltubercidin—were evaluated as potential CA II inhibitor scaffolds using an integrated in silico strategy, with AZM as reference. SwissADME analysis showed all derivatives to be within an acceptable small-molecule space, with higher molecular weights (345–425 g/mol) and polarity than AZM (208.22 g/mol), yet comparable TPSA values for psammaplin C, 5′-O-sulfamoyltubercidin, and 5′-O-sulfamoyladenosine (150–197 Ų vs. 151.66 Ų). ADMET predictions indicated uniformly low gastrointestinal absorption, lack of blood–brain barrier permeability, non-substrate behavior for P-glycoprotein, and no CYP450 inhibition. PASS analysis revealed markedly higher predicted anticancer activity for 5′-O-sulfamoyl-2-chloroadenosine, 5′-O-sulfamoyladenosine, and 5′-O-sulfamoyl-2-bromoadenosine (Pa up to 0.927; IAP > 0.89) compared with AZM. Molecular docking showed all derivatives binding CA II at least as well as AZM (−6.7 kcal/mol), with top scores for 5′-O-sulfamoyl-2-chloroadenosine (−8.0 kcal/mol), 5′-O-sulfamoyl-2-bromoadenosine (−7.8 kcal/mol), and 5′-O-sulfamoyltubercidin (−7.7 kcal/mol), supported by extensive hydrogen bonding and hydrophobic contacts. Collectively, these nucleoside-based primary sulfamates emerge as promising natural scaffolds for next-generation CA II-targeted therapeutics.