A fine-tuning-guided virtual screening workflow identifies cell-active small-molecule hits targeting Gq-mediated...

Gq protein represents a critical signaling node in GPCR pathways, its abnormal activation relates with various diseases, including uveal melanoma and cardiovascular disorders. However, existing Gq inhibitors suffer from structural complexity and poor drug-like properties, while traditional screening methods have proven inefficient for discovering novel chemotypes. Here, we developed a prioritization workflow that combines target-specific fine-tuning of a pretrained drug-target interaction model, pharmacophore filtering, and structure-based docking to identify candidate Gq-modulating compounds from commercial libraries. MST measurements provided preliminary evidence of interaction with Gαq-containing preparations for a subset of the cell-active compounds. Subsequent cellular evaluations indicated that these compounds modulate Gq heterotrimer dissociation and downstream signaling under the tested assay conditions. This work provides early Gq-modulating hit compounds with chemically distinct scaffolds and illustrates a practical workflow in which target-specific model fine-tuning can be combined with structural filtering and orthogonal experimental evaluation for drug discovery.