BCover: An Electronic Structure-Based Scoring Suite for Reaction-Aware Covalent Docking

Abstract

Covalent virtual screening requires ranking compounds according to both noncovalent recognition and their ability to adopt a reaction-competent geometry with an appropriately reactive warhead. Here, we introduce BCover, a reaction-aware scoring suite that combines pre-reactive docking with quantum-chemistry-derived ligand reactivity descriptors, the electrostatic properties of the protein pocket. Quantum-chemical descriptors are aggregated using a nonlinear tree-based scoring model. BCover was evaluated retrospectively on the COValid benchmark, comprising nine targets and ten reactive sites, and compared with AutoDock, DOCK6, DOCKovalent, AlphaFold3 with Rosetta rescoring, and AlphaFold3 confidence-based ranking. BCover achieved an average adjusted LogAUC of 31% (57% max), an average ROC-AUC of 0.88 (0.96 max), an average EF1 of 18 (33 max). Its average LogAUC exceeded those of the classical docking methods and AlphaFold3-Rosetta, although AlphaFold3-mPAE provided the strongest overall enrichment. At an average runtime of about 10~s per ligand, BCover was approximately 25-fold faster than the evaluated AlphaFold3 workflows and achieved the highest average time-adjusted virtual-screening productivity index. Redocking experiments further showed that the method recovered near-native ligand conformations. These results demonstrate that combining docking-derived geometry with ligand local electronic reactivity and pocket electrostatics provides an efficient and interpretable strategy for covalent ligand prioritization. BCover is intended as a high-throughput screening method that complements more computationally demanding QM/MM and free-energy calculations during subsequent lead optimization.