DESPOT: Direction-Enhanced Scoring POTentials for Scoring of Protein-Ligand Interactions

Abstract Knowledge-based potentials (KBPs) have long been used to score protein–ligand interactions, yet existing formulations remain isotropic, capturing only distance dependencies and neglecting the directional preferences that govern molecular recognition. Here, we introduce Direction-Enhanced Scoring POTentials (DESPOT), an anisotropic knowledge-based framework that unifies pose scoring and binding-site characterisation within a single probabilistic model. The new probabilistic formulation used in DESPOT naturally supports directional modelling through atom type–specific local reference frames and symmetry-aware geometric discretisation. It also supports steric exclusion, encoded as a dedicated void state that explicitly captures the probability that a spatial bin remains unoccupied. The anisotropic interaction profiles learned by DESPOT reveal systematic directional preferences for interactions such as hydrogen bonds, aromatic interactions, and halogen bonds, that extend beyond idealised geometric models. Evaluation on the CASF-2016 benchmark shows that DESPOT sub-stantially outperforms isotropic KBPs in all pose-discrimination and virtual screening tasks (p ≪ 0.0001 for all enrichment factors), with the largest gains arising from its ability to penalise geometrically implausible poses. Constrained energy minimisation of training structures proves strongly beneficial for the derivation of KBPs, while our train–test leakage analysis reveals that overfitting is an underestimated and understudied issue for KBPs. DESPOT provides a data-driven framework for direction-aware modelling of protein–ligand interactions, with applications in pose scoring, binding-site characterisation, and structure-based design. Competing Interest Statement The authors have declared no competing interest.