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

arXiv · AI, language, vision and robotics · article · Sep 2, 2026 · UTC

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

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