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FLOWR.ROOT - A flow matching-based foundation model for joint multi-purpose structure-aware 3D ligand generation and affinity prediction.
Nat. Commun. 17:5883 (2026)
We present FLOWR.ROOT, an SE(3)-equivariant flow-matching foundation model that unifies pocket-aware 3D ligand generation with multi-endpoint binding affinity prediction (pIC50, pKi, pKd, pEC50) and pLDDT-based confidence estimation in a single backbone. One trained model supports de novo pocket-conditional generation, interaction- and pharmacophore-conditional sampling, scaffold hopping and elaboration, and fragment growing or replacement, enabled by a mixed isotropic-anisotropic prior placement strategy. Training proceeds in three stages: large-scale pre-training on billions of ligand conformations and millions of mixed-fidelity protein-ligand complexes, refinement on curated co-crystal data, and project-specific adaptation via parameter-efficient LoRA finetuning. Joint structure-affinity modelling enables inference-time importance-sampling guidance for single- and multi-objective design without external scoring functions. Case studies on kinase selectivity (CK2α/CLK3) and scaffold elaboration on TYK2, ERα, and BACE1 illustrate utility from hit identification through lead optimization.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Efficient; Inhibitor; Accuracy; Database; Docking
ISSN (print) / ISBN
2041-1723
e-ISSN
2041-1723
Journal
Nature Communications
Quellenangaben
Volume: 17,
Issue: 1,
Article Number: 5883
Publisher
Springer
Publishing Place
London
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)
Grants
Helmholtz Munich
Pfizer Worldwide Research and Development
Pfizer Worldwide Research and Development