QSARINS-Based Development of Predictive Models for Aryl Sulphonamide Derivatives as Dual Enzyme Inhibitors

Objective: To develop and validate QSAR models of aryl sulphonamide derivatives for predicting dual inhibitory activity against Carbonic Anhydrase II and Acetylcholinesterase. Methods: Aryl sulphonamide derivatives were analysed using QSARINS software. Molecular descriptors were calculated via PaDEL, followed by Multiple Linear Regression (MLR) model generation. Models were validated through internal (LOO, LMO) and external (test set) statistics, alongside Y-scrambling for robustness. Descriptor selection ensured elimination of collinearity. Predicted inhibitory activities were compared with experimental pIC50 values to confirm model reliability and predictive performance. Findings: QSAR models developed for aryl sulphonamide derivatives demonstrated strong predictive power for dual inhibition of Carbonic Anhydrase II (CA II) and Acetylcholinesterase (AChE). The best CA II model showed R2 = 0.86, Q2 = 0.79, and external R2pred = 0.81, while the AChE model achieved R2 = 0.83, Q2 = 0.76, and R2pred = 0.79, confirming robustness and high predictive accuracy. Y-scrambling validated model reliability by eliminating chance correlations. Significant descriptors such as WTPT, BCUT, and electronic charge indices revealed that extended conjugation and specific electronic features enhance dual inhibitory activity. These findings align with existing reports emphasising the electronic influence of sulphonamide derivatives but provide a novel insight by correlating topological descriptors with dual-target inhibition. The developed models offer a valuable framework for designing new multifunctional agents targeting neurodegenerative and metabolic disorders, improving efficiency in lead optimisation and reducing the need for extensive experimental screening. Novelty: This study uniquely correlates topological and electronic descriptors of aryl sulphonamides with dual inhibition of CA II and AChE, offering predictive models for multifunctional drug design. Keywords: QSARINS, Carbonic Anhydrase II, Acetylcholinesterase, Dual-target inhibitors, Molecular descriptors, Validation