AlphaFold2 structures guide prospective ligand discovery.

Journal: Science (New York, N.Y.)
Published Date: Jun 21, 2024

Abstract

AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental and AF2 structures, as were affinities. Success in docking against the AF2 models was achieved despite differences between orthosteric residue conformations in the AF2 models and the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5-HT2A 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 drug design.

Authors

  • Jiankun Lyu
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
  • Nicholas Kapolka
    Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Ryan Gumpper
    Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Assaf Alon
    Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Liang Wang
    Information Department, Dazhou Central Hospital, Dazhou 635000, China.
  • Manish K Jain
    Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Ximena Barros-Álvarez
    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94035, USA.
  • Kensuke Sakamoto
    Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Yoojoong Kim
    School of Electrical Engineering, Korea University, Seoul, South Korea.
  • Jeffrey DiBerto
    Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Kuglae Kim
    Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Isabella S Glenn
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
  • Tia A Tummino
    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
  • Sijie Huang
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
  • John J Irwin
    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
  • Olga O Tarkhanova
    Chemspace LLC, Kyiv 02094, Ukraine.
  • Yurii Moroz
    Chemspace LLC, Kyiv 02094, Ukraine.
  • Georgios Skiniotis
    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94035, USA.
  • Andrew C Kruse
    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Andrew_Kruse@hms.harvard.edu.
  • Brian K Shoichet
    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
  • Bryan L Roth
    National Institute of Mental Health, Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, United States.

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