Virtual screening, molecular dynamics, and binding free energy calculations on human carbonic anhydrase IX catalytic domain for deciphering potential leads.

Carbonic anhydrase IX is a tumor-associated membrane-bound metallo-enzyme which catalyzes the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3-) and proton (H+) ions. It is a hypoxia-inducible enzyme and plays a critical role in tumor pH homeostasis favoring tumor cell invasiveness and drug resistance. Over expression of CAIX is documented in cancers of breast, lung, kidney, colon/rectum, etc. Chemical inhibition of CAIX activity has proven to be an effective therapeutic modality towards targeting cancer. Hence, in this study, we intend to identify potential molecules from NCI (National Cancer Institute) and Maybridge databases implementing high-throughput virtual screening. CAIX co-crystallized with acetazolamide (a known inhibitor of CAIX) (PDB ID: 3IAI) was used for reference-guided docking protocol. The potential inhibitors among the coupled data sets were finalized based on Glide docking score, Prime/MMGBSA scoring, significant intermolecular interactions, ADMET (absorption, distribution, metabolism and excretion, toxicity) prediction and stability of complex formation, molecular dynamics simulation, and comparative analysis. By this study, we propose NSC_93618, NSC_170253, NSC_93618, JFD03677, SEW06488, and BTB09372 to be highly significant, as all these compounds were found to qualify as potential leads surpassing all the stringent filtering process. However, NSC_93618 was found to be the most potential, as it featured with higher complex stability with strong bonded interactions, binding affinity synonymous to acetazolamide. Hence, these proposed compounds shall prove to be effective in targeting CAIX towards modulating carcinogenesis.