<br/>Carbonic anhydrases(CA) are zinc metalloenzymes which catalyze the reversible hydration of carbon dioxide via nucleophilic attack and removal of proton from the active site. There are about 15 different isoforms of CA found in humans with different gene expression profiles, locations in the cell and functionality such as muscle contraction, renal acidification, gluconeogenesis. Among these isoforms, CAIX and CAXII are accountable for the proliferation of tumor cells. Several studies have been conducted to inhibit them without affecting the other CA enzymes. The similarity in these CA enzymes makes the process of finding inhibitors significantly difficult. Experimentally, it has been found that Acesulfame K, an FDA approved food additive selectively inhibits CAIX enzyme without affecting CAII. This difference was attributed to residue 131(Phe in CAII and Val in CAIX) due to the bulky nature of the amino acid. However, similar inhibition was not seen in CAXII which has an alanine in the same position. In this work, the difference of binding energies of the Ace K conformations in CAII and CAIX is evaluated using QM/MM umbrella sampling simulations. Through our simulations, we are able to replicate the experimental binding conformations of the ligand in CAII and CAIX. We aim to study the interactions responsible for these differences in binding of the CA inhibitors for future drug discovery.<br/>

Relative binding affinity of an inhibitor to two human carbonic anhydrase isozymes

2019 Spring National Meeting

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