A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins
Suzanne Ackloo, Fengling Li, Magda Szewczyk, Almagul Seitova, P. Loppnau, Hong Zeng, Jin Xu, Shabbir Ahmad, Yelena A. Arnautova, Arrash J. Baghaie, Serap Beldar, Albina Bolotokova, Paolo A. Centrella, Irene Chau, Matthew A. Clark, John W. Cuozzo, Saba Dehghani-Tafti, Jeremy S. Disch, Aiping Dong, Antoine Dumas, Jianwen A. Feng, Pegah Ghiabi, Elisa Gibson, Justin Gilmer, Brian Goldman, Stuart R. Green, Marie-Aude Guié, John P. Guilinger, Nathan Harms, Oleksandra Herasymenko, Scott Houliston, Ashley Hutchinson, Steven Kearnes, Anthony D. Keefe, Serah Kimani, Trevor J. Kramer, Maria Kutera, Haejin Angela Kwak, Cristina Lento, Yanjun Li, Jenny Liu, Joachim Loup, Raquel A. C. Machado, Christopher J. Mulhern, Sumera Perveen, Germanna Lima Righetto, Patrick Riley, Suman Shrestha, Eric A. Sigel, Madhushika Silva, Michael D. Sintchak, Belinda L. Slakman, Rhys Dylan Taylor, James Thompson, Wen Torng, Carl Underkoffler, Moritz von Rechenberg, Ryan T. Walsh, Ian R. Watson, Derek J. Wilson, Esther Wolf, Manisha Yadav, Aliakbar Khalili Yazdi, Junyi Zhang, Ying Zhang, Vijayaratnam Santhakumar, A.M. Edwards, Dalia Barsyte-Lovejoy, Matthieu Schapira, Peter J. Brown, Levon Halabelian, C.H. Arrowsmith
Abstract
Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.