Year: 2026
Type: preprint
Abstract: Superposing one small molecule onto another is routine in ligand-based drug discovery. In atom-level correspondence methods, the pose the correspondence determines is only a starting point, and a subsequent search produces what is reported. We present ShapeAligner, a rigid aligner whose output pose is the superposition its maximal clique correspondence determines. Maximal cliques of an association graph over chemically typed heavy atoms each fix a reflection-free, equally weighted Kabsch transform in closed form. An analytic Gaussian shape-and-color volume overlap ranks the resulting poses. Nothing after the superposition moves the pose. Across 68,150 directed tasks from the LOBSTER cross-pair corpus, the top pose lands within 2.0 Å of the crystallographic pose in 30.98% of the tasks ShapeAligner covers, against 28.32% for the next-highest of six comparators. The median time is 0.214 s per task on one CPU core. Recovery depends strongly on the pair. It is highest when the larger ligand serves as the template, and the two ligands share at least 0.60 of the smaller ligand's volume. Below that threshold no method recovers more than 4% of the tasks it covers. The output is deterministic, and the correspondence it rests on is invariant to the input coordinate frame by construction. The implementation is released under the MIT license.
Source: ChemRxiv
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7211880641