Unlocking NewComputational Insights into Novel Inhibitors: Virtual Screening of Small Molecules against Human Carbonic Anhydrase II

Balamurali MM^*Sermarajan ArunachalamRamachandran Gnanasekaran

• VIT Chennai, Chennai, India

Carbonic anhydrases, a zinc based metalloprotein facilitates the reversible conversion of CO2 into carbonic acid when transported through blood vessels and subsequently regulates the physiological pH. In humans, this enzyme has been the therapeutic target for numerous diseases, as its abnormal regulation leads to a variety of disorders. Regulatory mechanism of this enzyme includes targeting of catalytic Zn2+ ion as well as the residues that significantly regulate the protein's structure and stability. Numerous inhibitors derived fromWith the available data on numerous sulfonamides, sulfamates, sulfamidessulphamates, sulphamides and non-sulphamide derivatives were reportedderived inhibitors, in the recent past. Hereinthis study, a library of sulphonamide, extended aromatic sulphonamide and non-sulphonamide derivatives were identified from multiple sources and their inhibition potential were evaluated followingwas screened using a fragment-based drug discovery approach. Virtual screening was performed with molecular docking (DOCK6 and Schrödinger GLIDE), rescored using MM-GBSA and validated over 100 ns molecular dynamicdynamics simulations. Further pharmacophoricPharmacophore models were developed to identify key interaction features, while pharmacokinetic profiles were evaluated to assess their drug-likeness. Compounds S8 (sulphonamide) and S15–S16 (non-sulphonamides) emerged as promising inhibitors, showing strong Zn²⁺ coordination, stable binding to residues His93, Leu196, Thr197 and Thr198 that favour pharmacokinetic properties were investigated. The results provide atomistic insights into CAII inhibition and identify potential leads for evaluating their druggabilityfurther experimental validation.