Data Sheet 1_Structure-based virtual screening for TRPM8 modulators.pdf

Transient receptor potential melastatin 8 (TRPM8) is an emerging therapeutic target, yet the performance of available structural models for docking and optimal docking protocols for virtual screening (VS) remains unclear. Here, we benchmarked two available TRPM8 structural conformations (agonist-bound TRPM87WRE and antagonist-bound TRPM89B6G) using docking tools, Smina and rDock, using known TRPM8 inhibitors and property-matched decoys. rDock achieved the highest hit rates and outperformed Smina in ranking true actives at first-ranks than their corresponding decoys, whereas Smina showed a target-structure dependence on docking performance but delivered superior overall ranking quality across both target structures. Both docking tools displayed considerable overlap between active and decoy score distributions, indicating only moderate discriminatory power of docking scores alone. When prioritizing a small subset of top-ranked compounds, integrated screening approaches, particularly the consensus protocol, improved the recovery of true actives, while the hierarchical protocol achieved comparable performance at a substantially lower computational cost. Collectively, this work establishes a reproducible VS benchmark for TRPM8 and supports the use of different screening protocols to improve early hit identification.