Steroids interfere with human carbonic anhydrase activity by using alternative binding mechanisms

Bile acids have been shown to inhibit human (h) carbonic anhydrases (CA, EC 4.2.1.1) along the gastro-intestinal tract, including hCA II. The elucidation of the hormonal inhibition mechanism of the bile acidcholate to hCA II was provided in 2014 by X-ray crystallography. Herein, we extend the inhibition study toa wealth of steroids against four relevant hCA isoforms. Steroids displaying pendants and functionalgroups of the carboxylate, phenolic or sulfonate types appended at the tetracyclic ring were shown toinhibit the cytosolic CA II and the tumor-associated, transmembrane CA IX in a medium micromolar range(38.9–89.9mM). Docking studies displayed the different chemotypes CA inhibition mechanisms. Moleculardynamics (MD) gave insights on the stability over time of hyocholic acid binding to CA II.