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

Publication Type:

Journal Article

Authors:

Ahmad, Shabbir; Xu, Jin; Feng, Jianwen A; Hutchinson, Ashley; Zeng, Hong; Ghiabi, Pegah; Dong, Aiping; Centrella, Paolo A; Clark, Matthew A; Guié, Marie-Aude; Guilinger, John P; Keefe, Anthony D; Zhang, Ying; Cerruti, Thomas; Cuozzo, John W; von Rechenberg, Moritz; Bolotokova, Albina; Li, Yanjun; Loppnau, Peter; Seitova, Alma; Li, Yen-Yen; Santhakumar, Vijayaratnam; Brown, Peter J; Ackloo, Suzanne; Halabelian, Levon

Source:

J Med Chem, Volume 66, Issue 23, p.16051-16061 (2023)

Keywords:

DNA, Gene Library, Ligands, Machine Learning, Small Molecule Libraries

Abstract:

<p>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 , with a of 6 &plusmn; 2 μM by surface plasmon resonance. The co-crystal structure confirmed the binding of to the WDR91 side pocket, in proximity to cysteine 487, which led to the discovery of covalent analogues and . The covalent adduct formation for and was confirmed by intact mass liquid chromatography-mass spectrometry. The discovery of , , and , 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.</p>

PDB: 
8SHJ, 8T55
Detector: 
EIGER
Beamline: 
24-ID-E