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Research questionHow can structure-based lead optimization improve target affinity without increasing off-target binding when off-target structures are unknown?Affinity-focused lead optimization can produce compounds that bind unintended pockets, while specificity-aware approaches often depend on structural information about those off-targets. The challenge is improving binding to a known target while limiting unintended interactions when off-target structures are unavailable.
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Research Paper
Latest papersRecent research connected to this question, newest first.SurfSpec: Enhancing Off-Target-Agnostic Specificity by Bounding Pocket-Ligand Geometric MismatchThe evidence concerns SurfSpec, which grows ligands toward under-occupied regions of the target-pocket surface and refines them with a pocket-conditioned ligand prior. On the CrossDocked2020 test set, it reports reduced geometric mismatch, higher empirical specificity than evaluated off-target-agnostic baselines, and competitive target-affinity improvement. The abstract also describes a conservative specificity lower bound for geometrically separated off-targets based on geometric mismatch and empirical geometry–affinity calibration.research paper · Sep 2, 2026
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