From Tapinarof to Novel AhR Modulators: Computational Drug Discovery for Psoriasis Therapeutics

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor involved in the regulation of many patho-physiological processes. Among these, immune system modulation, as well as regulation of skin homeostasis and inflammation, make it a promising target for psoriasis therapy. Tapinarof, an AhR agonist recently approved for psoriasis treatment, exerts its action through antioxidant, anti-inflammatory and barrier-restoring effects. In this study, we employed a computational drug-discovery approach to identify novel AhR modulators with psoriasis therapeutic potential. We performed a multi-step similarity-based screening in PubChem. Application of molecular docking led to the identification of diverse chemical scaffolds with high docking scores and potential AhR activity, some of which belong to chemical classes with known pharmacological relevance. Notably, several identified compounds suggest a possible interplay between AhR signaling and sirtuin modulation, highlighting a previously unexplored avenue in psoriasis therapy. Our findings underscore the potential of computational approaches in accelerating the discovery of novel AhR-targeting agents and provide a foundation for further experimental validation.