Computational Identification of Natural Product–Based Aryl Hydrocarbon Receptor Modulators for Psoriasis Therapy
نویسندگان
1 Department of Pharmacy Practice, Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad 244001, India
2 Department of Pharmacognosy, Arulmigu Kalasalingam College of Pharmacy, Krishnankoil Tamil Nadu, India
3 Department of Regulatory Affairs, Ricon Pharma LLC, 100 Ford Rd, Suite 9, Denville, NJ 07834, USA
4 Department of Pharmaceutical Analysis, Malla Reddy Institute of Pharmaceutical Sciences, Malla Reddy Vishwavidyapeeth (Deemed to be University), Secunderabad, 500100, Telangana, India
5 School of Pharmacy, ITM University, Turari Campus, Jhansi Road, Gwalior, Madhya Pradesh, India
6 Department of Pharmacology, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishnapuram, Pallavaram, Chennai, Tamil Nadu 600117, India
7 Department of Regulatory Affairs, InvaGen Pharmaceuticals, A Cipla subsidiary, 550 South Research Place, Central Islip, USA
8 Department of Regulatory Affairs, Hikma Pharmaceuticals USA, Inc.,2 Esterbrook Lane, Cherry Hill, NJ 08003, USA
doi
10.48309/chemm.2026.563458.2054چکیده
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.
