Halogenated Phenylsulfamates as hCA IX Inhibitors: In Silico Evaluation of Dynamic Stability and Pharmacokinetic Safety

ABSTRACT

Therapeutic targeting of human Carbonic Anhydrase IX (hCA IX) is critical for cancer treatment, as the enzyme regulates pH homeostasis and facilitates the survival of hypoxic tumor cells. This in silico study presents a multi‐layered computational investigation of a series of 4‐halogenated phenylsulfamates (4: Cl, 5: Br, 6: I) to evaluate their potential as next‐generation inhibitors. Integrated ADME and toxicological profiling predicted strong drug‐like properties, including high gastrointestinal absorption and a favorable safety profile. Specifically, the series exhibits an optimized lipophilic–hydrophilic balance required for effective systemic distribution. Molecular docking and MM‐GBSA binding free energy calculations revealed a clear structure–activity relationship, where para‐halogen substitution maximizes occupancy of the hydrophobic catalytic pocket. Molecular dynamics (100 ns) simulations were employed to evaluate binding stability relative to the clinical standard acetazolamide (AAZ). The lead candidate, 4‐chlorophenyl sulfamate (4), demonstrated enhanced dynamic persistence, maintaining robust Zn‐coordination and a stable hydrogen bond with the gatekeeper residue Thr199 for 99% of the trajectory. It remained in a rigid binding pose (Lig fit on Prot RMSD ∼1.25 Å), suggesting high structural integrity compared to the clinical benchmark. The optimized phenylsulfamate scaffold confers significant stability, identifying these halogenated derivatives as promising leads for future experimental validation.