Ligand-Based Pharmacophore Modeling and Quantum Computational Approaches for the Development of hCA XII Inhibitor.

Globally, there is a threat to public health regarding the prevalence of cancer and its resistance problem. Among the various cancer therapy strategies, targeting Carbonic anhydrase (CA) has gained a lot of attention in recent times. CA XII was found to be a biomarker for the suppression of various hypoxic tumors in both the early and metastatic stages. This work aims to identify new lead CA XII inhibitors without inhibiting other isoforms and to replace the benzene sulfonamide scaffold. Existing lead molecules were computationally investigated, screened, and subjected to pharmacokinetic studies, molecular docking, DFT, and molecular dynamics simulation. A pharmacophore model was developed from the existing CA inhibitors, and 43 hit molecules were identified. All the hit molecules passed ADMET, and the molecular docking results revealed that among the identified novel CA inhibitors, compounds 3 and 26 showed promising leads with low energy conformation (-7.82 K/Cal and -7.36 K/Cal) and subsequently provided structural insights against target inhibition compared to the standard drug acetazolamide. RMSD and RMSF values followed by MMGBSA calculations revealed that compounds 3 and 26 are more stable than the standard. The study concludes that compounds 3 and 26 can be a new lead for CA XII inhibition.