Scaffold hopping from deposited crystal pairs: docking-free contact-conservation benchmark and structure-validated method
Year: 2026
Type: preprint
Abstract: Scaffold hopping—replacing a ligand core while retaining function—is almost always scored by two-dimensional similarity to the reference, by docking to a single pose, or by recovery of one literature ligand, while the trivial baseline of copying the reference decorations is rarely reported. We build a benchmark from the Protein Data Bank: 2,886 ligand pairs that bind the same pocket with different Bemis–Murcko scaffolds, across 27 targets and five families, with scaffold- and target-held-out splits. Superposing the two crystal structures and transferring the experimentally solved hop into the reference pocket gives a docking-free contact-conservation criterion: the true hop recovers 80.6% of reference contacts across 40 crystal pairs, and 97% of pairs exceed 0.6; the criterion tracks pharmacophore overlap (ρ = 0.51, n = 50) but not the potency gap (ρ = −0.13), so it measures pose, not affinity. SV-Hop (structure-validated scaffold hopping)—a 60,069-rule core-replacement lexicon, exact graph swap, property/SA/novelty constraints and a learned contact ranker—returns a novel, property-conserved, synthesizable hop for 62.1% of 298 scaffold-held-out references, against 50.3% (property), 44.3% (2D), 27.0% (random) and 0% (copy). The scaffold split holds out scaffolds rather than pockets, so 97.4% of test pairs share a pocket with training; under target shift the gain falls to +5.3 pp (65.3% vs 60.0%) and the ranker transfers weakly (ρ = 0.13). A 388-rule PDB-only lexicon matches coverage and reaches 81.9% on the same target-held-out split, against 65.3% for the full lexicon, and an equal-diversity control attributes part but not all of that gap to candidate diversity. We release the benchmark, lexicon, model and a 22-compound prospective panel.
Source: ChemRxiv
Authors: Xiongjie Xiao, Yi Huang, Bin Jiang, Xu Zhang, Maili Liu
Institutions: Chinese Academy of Sciences, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan National Laboratory for Optoelectronics, Optics Valley Laboratory, Huazhong University of Science and Technology
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225746657
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