2. Academic Validation
  3. AlphaFold2 structures guide prospective ligand discovery

AlphaFold2 structures guide prospective ligand discovery

  • Science. 2024 May 16:eadn6354. doi: 10.1126/science.adn6354.
Jiankun Lyu # 1,  Nicholas Kapolka # 2,  Ryan Gumpper # 2,  Assaf Alon # 3,  Liang Wang # 4,  Manish K Jain 2,  Ximena Barros-Álvarez 4,  Kensuke Sakamoto 2 5,  Yoojoong Kim 2,  Jeffrey DiBerto 2,  Kuglae Kim 2,  Isabella S Glenn 1,  Tia A Tummino 1,  Sijie Huang 1,  John J Irwin 1,  Olga O Tarkhanova 6,  Yurii Moroz 6 7 8,  Georgios Skiniotis 4 9,  Andrew C Kruse 3,  Brian K Shoichet 1,  Bryan L Roth 2 5 10
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
  • 2 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94035, USA.
  • 5 National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 6 Chemspace LLC, Kyiv 02094, Ukraine.
  • 7 Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine.
  • 8 Enamine Ltd., Kyiv 02094, Ukraine.
  • 9 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94304, USA.
  • 10 Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • # Contributed equally.
PMID: 38753765 DOI: 10.1126/science.adn6354
Abstract

AlphaFold2 (AF2) models have had wide impact, but they have had mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ2 and 5-HT2A receptors, testing hundreds of new molecules and comparing results to docking against the experimental structures. Hit rates were high and similar for the experimental and the AF2 structures, as were affinities. The success of docking against the AF2 models was achieved despite differences in orthosteric residue conformations versus the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based ligand discovery.

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