AlphaFold2 structures guide prospective ligand discovery-Reference-Cited by-同舟云学术

AlphaFold2 structures guide prospective ligand discovery

Published:2024-06-21 Issue:6702 Volume:384 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Lyu Jiankun¹²^ORCID,Kapolka Nicholas³^ORCID,Gumpper Ryan³,Alon Assaf⁴^ORCID,Wang Liang⁵^ORCID,Jain Manish K.³^ORCID,Barros-Álvarez Ximena⁵^ORCID,Sakamoto Kensuke³⁶^ORCID,Kim Yoojoong³,DiBerto Jeffrey³^ORCID,Kim Kuglae³^ORCID,Glenn Isabella S.¹^ORCID,Tummino Tia A.¹^ORCID,Huang Sijie¹,Irwin John J.¹^ORCID,Tarkhanova Olga O.⁷^ORCID,Moroz Yurii⁷⁸⁹^ORCID,Skiniotis Georgios⁵¹⁰^ORCID,Kruse Andrew C.⁴^ORCID,Shoichet Brian K.¹^ORCID,Roth Bryan L.³⁶¹¹^ORCID

Affiliation:

1. Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.

2. The Evnin Family Laboratory of Computational Molecular Discovery, The Rockefeller University, New York, NY 10065, USA.

3. Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.

4. Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.

5. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94035, USA.

6. 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.

7. Chemspace LLC, Kyiv 02094, Ukraine.

8. Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine.

9. Enamine Ltd., Kyiv 02094, Ukraine.

10. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94304, USA.

11. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

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 2 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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adn6354

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