A-P.13: Structure-based virtual screening for TRPM8 modulators
Since its discovery as the primary cold-sensing ion channel, the Transient Receptor Potential Cation Channel Melastatin Member 8 (TRPM8) has emerged as an attractive therapeutic target for cancer, pain, respiratory, and immune disorders. Although the underlying molecular mechanisms of temperature sensing and ligand recognition remain elusive, high-resolution structures of TRPM8 in agonist- and antagonist-bound conformations have been determined, enabling structure-based drug discovery approaches such as virtual screening (VS). However, systematic benchmarking of TRPM8 structural models and docking protocols has not yet been performed. Here, we establish a reproducible VS benchmark for TRPM8 by evaluating two high-resolution structures representing agonist-bound (TRPM87WRE) and antagonist-bound (TRPM89B6G) conformations using the open-source docking tools Smina and rDock with experimentally reported TRPM8 inhibitors and property-matched decoys. In addition, we investigated how different docking strategies can be combined to improve early hit identification.
rDock achieved higher hit rates and ranked true actives first among their corresponding decoy sets, whereas Smina showed stronger dependence on the target structure but provided better overall ranking quality across both conformations. Both docking tools displayed considerable overlap between active and decoy score distributions, indicating the limited discriminatory power of docking scores alone. When prioritizing a small subset of top-ranked compounds, integrated screening approaches improved recovery of true actives. Notably, the hierarchical protocol achieved performance comparable to consensus protocol while requiring substantially lower computational cost. Together, this work establishes the first systematic VS benchmark for TRPM8 and highlights the importance of integrated docking workflows for scalable hit discovery.
Co-authors: Pedro Ballester
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