Peer-Reviewed Publication
Nature2026September 16, 2026Journal Article
Development of a random background to understand ligand optimization.
Xinyu Xu1, Olivier Mailhot1, Galen J Correy2, Xi-Ping Huang3, Joao M Braz4, Da Shi5, Karthik Srinivasan1, Kara Zielinski2, Yuliia Holota6, Yuliia Kuziv6, Christos Iliopoulos-Tsoutsouvas7, Nathan D Levinzon8, Yagmur U Doruk9, Moira M Rachman1, Morgan E Diolaiti9, Maisie G V Stevens9, Fangyu Liu1, Katie L Holland1, Harald Hübner10, Jing Wang3, Yujin Wu1, Alan Ashworth9, Alexandros Makriyannis7, Yuqi Zhang5, Yurii S Moroz6,11,12, Peter Gmeiner10, Robert Abel13, Aashish Manglik1, Allan I Basbaum4, Bryan L Roth14, James S Fraser15, Brian K Shoichet16
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
3Department of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
4Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
5Schrödinger Inc., San Diego, CA, USA.
6Enamine Ltd., Kyiv, Ukraine.
7Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
8Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
9Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
10Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
11Chemspace LLC, Kyiv, Ukraine.
12Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
13Schrödinger Inc., New York, NY, USA.
14Department of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
15Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA. jaimefraser@gmail.com.
16Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA. bshoichet@gmail.com.
Abstract
Ligand optimization is central to drug discovery, with hundreds of analogues often designed and synthesized between an initial hit and a therapeutic candidate1,2. The efficiency of this process is unclear, partly because there is no random background for optimization to compare against. Such a random background might emerge from systematic random small substitutions across starting ligands, measur…
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