Computational Identification of Natural Product–Based Aryl Hydrocarbon Receptor Modulators for Psoriasis Therapy

Psoriasis is a chronic inflammatory disease of the skin that needs to be managed in the long term, and the aryl hydrocarbon receptor (AhR) has turned out to be an effective therapeutic target because of its ability to control keratinocyte differentiation and immune signaling. Based on the approved pharmacophore template named Tapinarof, a pharmacophore model was used to screen the ZINC Natural Products Library to identify alternative scaffolds. Three of them, ZINC69482103 (-11.132 kcal/mol), ZINC4098639 (-11.008 kcal/mol), and ZINC13485093 (-10.909 kcal/mol)), more strongly predicted binding to the AhR PAS-B domain than Tapinarof (-10.209 kcal/mol). These molecules also replicate the important aromatic stacking and hydrogen-bond interactions that are significant in the modulation of AhR. The molecular mechanics/generalized Boron surface area (MM-GBSA) analysis also confirmed their high binding potential with ZINC69482103, presenting a favorable ΔGbind value. Simulations of 100 ns using molecular dynamics (MD) ensured the stability of the interaction between the ligands and proteins, remaining at constant values of Root Mean Square Deviation (RMSD), and the contact profile was maintained during the simulation. Drug-likeness and bioavailability assessments with ADMETlab showed that all three compounds were within reasonable physicochemical ranges, with ZINC13485093 exhibiting the most moderate ADMET parameters. In general, the results identified three natural product scaffolds as potential candidates for the development of next-generation AhR modulators for the treatment of psoriasis, particularly ZINC69482103 and ZINC13485093. Their therapeutic potential should be validated through further experiments.