SurfSpec: Enhancing Off-Target-Agnostic Specificity by Bounding Pocket-Ligand Geometric Mismatch

תקציר מקורי באנגליתarXiv:2609.02963v1 Announce Type: cross Abstract: Lead optimization in structure-based drug design aims to improve target binding while avoiding unintended interactions with off-target pockets. However, existing affinity-driven methods do not explicitly control specificity, whereas current specificity-aware approaches commonly require prior knowledge of off-target structures. We address off-target-agnostic specificity-aware lead optimization by analyzing the geometric mismatch between a ligand and the target pocket. We provide a conservative specificity lower bound for geometrically separated off-targets without requiring access to off-target structures. By metricizing pocket--ligand mismatch, the triangle inequality shows that reducing target--ligand mismatch improves a conservative lower