ComTarget: Small-Molecule Target Prediction with Combinatorial Modeling

Background: Identifying potential targets for bioactive compounds is crucial for elucidating the mechanisms of action and drug development. Methods: This study presents ComTarget, a computational tool that integrates 3D molecular shape similarity analysis (based on combined 3D descriptors, C3DD) with reverse docking to predict protein targets for small molecules. ComTarget screens against a library of 4429 unique protein targets derived from 26,272 PDB complexes. Results: Validation on benchmark datasets (DEKOIS 2.0 and DUDE-Z) demonstrated that the C3DD molecular similarity calculation method effectively enriches active ligands by capturing critical 3D shape information not evident from chemical topology alone. It outperformed conventional 2D fingerprint methods and offered a favorable balance between shape sensitivity and computational efficiency, serving as a rapid pre-screening filter within the integrated workflow. For FDA-approved drugs (e.g., Imatinib, Aspirin) and natural products (e.g., Berberine). ComTarget identified targets consistent with reported therapeutic targets or putative off-targets in the literature, while also revealing potential targets aligned with the compounds’ pharmacological mechanisms. Conclusions: As a local program, ComTarget offers flexibility in computational resources customization and is freely available for polypharmacology studies, drug repurposing, and adverse reaction prediction.