Computational Insights into the Carbonic Anhydrase II Inhibitory Potential of Piperidin-4-one Based Curcuminoids: An Integrated Docking and DFT Study

As a predominant factor in permanent visual impairment, glaucoma management relies heavily on the systemic or topical modulation of intraocular pressure via Carbonic Anhydrase II (CA-II) inhibition. This investigation details the experimental evaluation and theoretical profiling of nine curcumin-inspired scaffolds functioning as non-sulfonamide CA-II antagonists. In vitro screening identified 3,5-bis[(2-hydroxyphenyl)methylidene]piperidin-4-one as the primary lead, demonstrating a remarkable inhibitory capacity of 81.44% and a sub-micromolar potency (IC₅₀​ = 7.92 µM). To resolve the molecular foundations of this activity, an integrated computational framework was employed, bridging molecular docking with conceptual Density Functional Theory (DFT). Simulation data indicate that high-affinity binding is contingent upon the ligand’s precision in navigating the catalytic cleft to establish essential stabilising networks with the Thr199 residue, effectively emulating the binding mode of clinical sulfonamides. Complementary DFT assessments confirm that inhibitory success is fundamentally governed by electronic reactivity descriptors. Specifically, the most efficacious derivatives are characterised by heightened nucleophilicity, elevated E_HOMO​ levels, and reduced chemical hardness (8.53 eV), which collectively facilitate transient electronic polarisation and efficient charge transfer toward the Zn²⁺ metal centre. These insights are further validated by Molecular Electrostatic Potential (MEP) topography, which underscores the requirement for electrostatic complementarity during the initial recognition phase. Ultimately, these findings position curcumin-based architectures as biocompatible and electronically optimised templates for the rational development of next-generation antiglaucoma therapeutics.