A resource to enable chemical biology and drug discovery of WDR Proteins
Author:
Ackloo SuzanneORCID, Li Fengling, Szewczyk Magda, Seitova Almagul, Loppnau Peter, Zeng Hong, Xu Jin, Ahmad Shabbir, Arnautova Yelena A, Baghaie AJ, Beldar Serap, Bolotokova Albina, Centrella Paolo A, Chau Irene, Clark Matthew A, Cuozzo John W, Dehghani-Tafti Saba, Disch Jeremy S, Dong Aiping, Dumas Antoine, Feng Jianwen A., Ghiabi Pegah, Gibson Elisa, Gilmer Justin, Goldman Brian, Green Stuart R, Guié Marie-Aude, Guilinger John P, Harms Nathan, Herasymenko Oleksandra, Houliston Scott, Hutchinson Ashley, Kearnes Steven, Keefe Anthony D, Kimani Serah W, Kramer Trevor, Kutera Maria, Kwak Haejin A, Lento Cristina, Li Yanjun, Liu Jenny, Loup Joachim, Machado Raquel AC, Mulhern Christopher J, Perveen Sumera, Righetto Germanna L, Riley Patrick, Shrestha Suman, Sigel Eric A, Silva Madhushika, Sintchak Michael D., Slakman Belinda L, Taylor Rhys D, Thompson James, Torng Wen, Underkoffler Carl, von Rechenberg Moritz, Watson Ian, Wilson Derek J, Wolf Esther, Yadav Manisha, Yazdi Aliakbar K, Zhang Junyi, Zhang Ying, Santhakumar Vijayaratnam, Edwards Aled MORCID, Barsyte-Lovejoy DaliaORCID, Schapira MatthieuORCID, Brown Peter J, Halabelian LevonORCID, Arrowsmith Cheryl HORCID
Abstract
AbstractProtein class-focused drug discovery has a long and successful history in pharmaceutical research, yet most members of druggable protein families remain unliganded, often for practical reasons. Here we combined experiment and computation to enable discovery of ligands for WD40 repeat (WDR) proteins, one of the largest human protein families. This resource includes expression clones, purification protocols, and a comprehensive assessment of the druggability for hundreds of WDR proteins. We solved 21 high resolution crystal structures, and have made available a suite of biophysical, biochemical, and cellular assays to facilitate the discovery and characterization of small molecule ligands. To this end, we use the resource in a hit-finding pilot involving DNA-encoded library (DEL) selection followed by machine learning (ML). This led to the discovery of first-in-class, drug-like ligands for 9 of 20 targets. This result demonstrates the broad ligandability of WDRs. This extensive resource of reagents and knowledge will enable further discovery of chemical tools and potential therapeutics for this important class of proteins.
Publisher
Cold Spring Harbor Laboratory
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