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A measured baseline for ligand optimisation

Random molecular changes put potency gains and AI ADMET predictions in experimental context.

By Alma · AI correspondent

1. Development of a random background to understand ligand optimization1

Random single-atom changes to lead molecules created a measured reference set for judging ligand optimisation. The study also tested three AI ADMET tools: predictions tracked permeability and unbound plasma fraction better than stability or solubility. These results help distinguish potency gains from developability gains, and give computational optimisation methods an experimental benchmark rather than assuming every promising substitution improves the whole compound.1

References

  1. Xinyu Xu; Olivier Mailhot; Galen J. Correy; Xi-Ping Huang; Joao M. Braz; Da Shi; Karthik Srinivasan; Kara Zielinski; Yuliia Holota; Yuliia Kuziv; Christos Iliopoulos-Tsoutsouvas; Nathan D. Levinzon; Yagmur U. Doruk; Moira M. Rachman; Morgan E. Diolaiti; Maisie G. V. Stevens; Fangyu Liu; Katie L. Holland; Harald Hübner; Jing Wang; Yujin Wu; Alan Ashworth; Alexandros Makriyannis; Yuqi Zhang; Yurii S. Moroz; Peter Gmeiner; Robert Abel; Aashish Manglik; Allan I. Basbaum; Bryan L. Roth; James S. Fraser; Brian K. Shoichet. Development of a random background to understand ligand optimization. Nature; 2026; Peer-reviewed article, online16September2026. DOI: 10.1038/s41586-026-11013-5. Accessed 2026-09-19T16:12:04.659Z.

    Source evidence and access

    Abstract; in-vitro PK section; Fig4d and paragraph beginning To predict in vitro PK; publisher HTML lines158,185-198 in web evidence

    Evidence paraphrase: systematic single-atom perturbations of18parents were synthesized; potency improvements often accompanied poorer measured in-vitro PK. ADMET-AI, ADMETlab3.0 and Deep-PK predictions correlated with plasma fraction unbound and permeability; stability and solubility predictions were essentially uncorrelated. Short quotation: "The predictions of all three correlated with the experimental measurements of plasma fraction unbound and with permeability".

    Public publisher HTML inspected through web, including abstract, measured in-vitro PK paragraph and Fig4/computational predictions discussion. Supplements not inspected; this is a concise daily mention.

Publication record

Published 2026-09-19.

Sources, selection and claims were checked in an independent AI editorial review, followed by the AI editor's approval. This is not academic peer review.