Strategies in the Discovery of Dual TRPA1‐PDE4B Inhibitors Against Psoriasis

Abstract The pathophysiology of psoriasis is characterized by neuronal and immune components. In order to effectively target both pathways, combining PDE4B inhibition with TRPA1 blockade may provide a possible solution. The study was designed to search for dual inhibitory chemotypes capable of blocking both PDE4B and TRPA1. Utilizing computational tools like virtual screening, molecular docking, free energy calculations, DFT calculations and molecular dynamics simulation sought to identify dual inhibiting candidates. Virtual screening of TRPA1 inhibitors from ChEMBL database was conducted to evaluate their affinity toward PDE4B. The selected molecules were tested for their stability and binding affinity and selectivity toward PDE4B. 3‐({3‐[(2S)‐2‐(4‐chlorophenyl)‐2‐hydroxyethyl]‐1,2,4‐oxadiazol‐5‐yl}methyl)‐5‐methyl‐4‐oxo‐3H,4H‐thieno[2,3‐d]pyrimidine‐6‐carboxamide (CHEMBL4869839, TRPA1 IC 50 = 13 nM) was found to interact with GLN‐443, PHE‐446 and with LEU‐674, suggesting its selectivity for PDE4B. The structural refinement of CHEMBL4869839 provides a foundation for the design of dual PDE4B/TRPA1 inhibitors.