Facilitating structure-based drug discovery with an artificial intelligence-driven virtual screening platform

Structure-based virtual screening (VS) via molecular docking is a pivotal approach for hit identification. Many artificial intelligence (AI)-powered protein-ligand docking and scoring methods have demonstrated impressive speed and accuracy. Retrospective benchmarking studies using enrichment rate and computational efficiency on curated datasets have corroborated their potential for discovering bioactive compounds. However, determining which method suits a specific application and implementing it efficiently remains challenging. Here we present the Comprehensive VS Platform with AI Engine (CVSP-AIE) for drug discovery from compound libraries. It integrates three AI models: KarmaDock, a fast docking model that directly updates atomic coordinates; CarsiDock, an accurate docking model that predicts protein-ligand distances and reconstructs binding poses; and RTMScore, an accurate scoring model that learns residue-atom distance distributions for affinity prediction. Their hierarchical application enables dynamical balances in screening speed and accuracy. CVSP-AIE is available as an online web server ( https://cadd.zju.edu.cn/cvsp/ ) and a local software package. Users can efficiently initiate drug screening by uploading a protein and a known binder that defines the binding pocket. The following workflow involves (1) preprocessing, including protein structure repair and molecule standardization, (2) binding pose and affinity prediction powered by KarmaDock, CarsiDock and RTMScore and (3) postprocessing, comprising protein-ligand interaction calculation and visualization. It takes 30-45 min to hierarchically screen 100,000 compounds, and the output is a ranked list of molecules with predicted binding scores, intermolecular interaction profiles and interactive chemical space analysis. Users can also install locally the hierarchical screening module through command-line package for arbitrary-scale screening.