<br/>Carbonic anhydrases(CA) are zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide via nucleophilic attack and, removal of a proton from the active site. There are 15 different isoforms of CA found in humans with distinct gene expression profiles, cellular locations and, functionality such as muscle contraction, renal acidification, gluconeogenesis. Among these isoforms, CAIX and CAXII are accountable for the proliferation of tumour cells. Several studies have been conducted to inhibit them without affecting the other CA enzymes. The similarities in the CA enzymes makes the process of designing CA selective inhibitors 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 the bulky nature of the amino acid present in the residue 131 (Phe in CAII and Val in CAIX). However, this explanation contradicts in CAXII, which doesn’t show similar inhibition even though small amino acid, alanine is present in the same position. In this work, the difference in the binding energies of the Ace K conformations in CAII and CAIX is evaluated using QM/MM umbrella sampling simulations. Additionally, through simulations, the experimental binding structures of the ligand in CAII and CAIX were replicated. Further through this study, we aim to understand the interactions responsible for the differences in the binding of the CA inhibitors for future drug discoveries.

Binding characteristics of an inhibitor to human carbonic anhydrase isozymes

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.