Plant-Derived Carbonic Anhydrase IV and IX Inhibitors: Predictive Pharmacodynamics and Therapeutic Potential

Abstract

Dermatological pathologies are multifactorial conditions that often show limited response to single-target therapies. Natural compounds may offer advantages through their pleiotropic effects on inflammation, oxidative stress, and tissue repair. This study employed an integrated in silico approach to evaluate selected phytoconstituents from Melaleuca alternifolia, Lavandula angustifolia, Tamarix ramosissima, and Curcuma longa. Drug-likeness, pharmacokinetic properties, dermal permeability, and toxicity were assessed using SwissADME and admetSAR 3.0. SwissTargetPrediction and the Similarity Ensemble Approach (SEA) identified carbonic anhydrases (CAs) among the predicted molecular targets, supporting the selection of CA IV and CA IX for structure-based analysis. Molecular docking identified favorable catalytic-site poses for several compounds, with curcuminoid and flavonoid scaffolds generally showing more favorable predicted affinities. Cyclocurcumin, tamarixetin, and scopoletin were subsequently investigated by molecular dynamics simulations. The simulations revealed scaffold- and isoform-dependent differences in interaction persistence: cyclocurcumin showed pronounced conformational flexibility, tamarixetin displayed more progressive displacement, and scopoletin showed the lowest persistence in the catalytic region. Overall, the results generate testable hypotheses regarding natural compound interactions with CA IV and CA IX, but experimental binding and enzymatic assays are required to establish CA modulation and therapeutic relevance.