2. Academic Validation
  3. Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning

Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning

  • J Med Chem. 2023 Dec 14;66(23):16051-16061. doi: 10.1021/acs.jmedchem.3c01471.
Shabbir Ahmad 1,  Jin Xu 2,  Jianwen A Feng 2,  Ashley Hutchinson 1,  Hong Zeng 1,  Pegah Ghiabi 1,  Aiping Dong 1,  Paolo A Centrella 3,  Matthew A Clark 3,  Marie-Aude Guié 3,  John P Guilinger 3,  Anthony D Keefe 3,  Ying Zhang 3,  Thomas Cerruti 4,  John W Cuozzo 4,  Moritz von Rechenberg 4,  Albina Bolotokova 1,  Yanjun Li 1,  Peter Loppnau 1,  Alma Seitova 1,  Yen-Yen Li 1,  Vijayaratnam Santhakumar 1,  Peter J Brown 5,  Suzanne Ackloo 1,  Levon Halabelian 1 6
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto, Ontario M5G 1L7, Canada.
  • 2 Google Research, Mountain View, California 94043, United States.
  • 3 X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02435, United States.
  • 4 Relay Therapeutics, 399 Binney Street, Cambridge, Massachusetts 02139, United States.
  • 5 Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 6 Department of Pharmacology and Toxicology, University of Toronto, Toronto M5S 1A8, Ontario, Canada.
PMID: 37996079 DOI: 10.1021/acs.jmedchem.3c01471
Abstract

WD40 repeat-containing protein 91 (WDR91) regulates early-to-late endosome conversion and plays vital roles in endosome fusion, recycling, and transport. WDR91 was recently identified as a potential host factor for viral Infection. We employed DNA-encoded chemical library (DEL) selection against the WDR domain of WDR91, followed by machine learning to predict ligands from the synthetically accessible Enamine REAL database. Screening of predicted compounds identified a WDR91 selective compound 1, with a KD of 6 ± 2 μM by surface plasmon resonance. The co-crystal structure confirmed the binding of 1 to the WDR91 side pocket, in proximity to cysteine 487, which led to the discovery of covalent analogues 18 and 19. The covalent adduct formation for 18 and 19 was confirmed by intact mass liquid chromatography-mass spectrometry. The discovery of 1, 18, and 19, accompanying structure-activity relationship, and the co-crystal structures provide valuable insights for designing potent and selective chemical tools against WDR91 to evaluate its therapeutic potential.

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