Molecular Modelling, Molecular Docking, Molecular Dynamic Simulations, MM-GBSA Study, and Pharmacokinetics Prediction of New Isatin-Sulfonamide Derivatives as Selective Carbonic Anhydrase CA IX Inhibitors

Abstract

Hypoxia within solid tumors triggers upregulation of carbonic anhydrase IX (CA IX), a key enzyme that maintains pH homeostasis and supports tumor survival, invasion, and therapy resistance. Selective CA IX inhibition is considered a promising anticancer strategy, but current inhibitors often lack isoform selectivity. This study aimed to synthesize a selective and potent CA IX inhibitor by designing a novel series of isatin-sulfonamide hybrid compounds. Five hybrid molecules were computationally assessed via molecular docking, General Born Surface Area (MM-GBSA) free energy calculations, and molecular dynamics simulations. Results identified Compound 3 as the most promising candidate, revealing strong binding affinity (docking score: –6.299 kcal/mol), a favorable free energy of binding (–28.24 kcal/mol), and stable interactions within the CA IX active site. Moreover, these hybrids exhibited enhanced toxicity profiles compared to the native ligand, with lower potential carcinogenicity and higher LD₅₀ values. The study concludes that isatin-sulfonamide hybrids, especially Compound 3, provide a Synergistic strategy for selectively disturbing hypoxic tumor metabolism, necessitating further experimental evaluation for development as anticancer agents.