3 years ago

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
Jeffrey W. Gross, Juan Wang, Carl A. Machutta, Yun Ding, Xiaopeng Bai, Thomas O’Keeffe, Yue Li, Heather P. O’Keefe, Pan F. Chan, David T. Fosbenner, Christina Pao, Svetlana Belyanskaya, Christopher R. Kwiatkowski, Jianzhong Huang, Jason W. Dodson, Jianghe Deng, Christopher C. Arico-Muendel, Patti McCormick, Lynn McCloskey, Walter P. Johnson, Ruth Lehr, Anthony E. Choudhry, David Barros-Aguirre, Sharon M. Sweitzer, Todd L. Graybill, Jean Zhang, Jing Chai, Jingye Zhou, Matt S. Steiginga, Gurdyal S. Besra, Amy Taylor, Robert H. Bates, Bing Xia, Devan J. Wilkins, Joël Lelièvre, Paolo A. Centrella, Kenneth E. Lind, Hongwei Qi, Gang Yao, Christopher S. Kollmann, May Fern Toh, Flora S. Sundersingh, Jeffrey A. Messer, Karen Ingraham, Christopher B. Phelps, Bryan W. King, Aaron Coffin, Xiaorong Liu, Christine P. Donahue, Sandy S. Chang, Lawrence M. Szewczuk, Genaro S. Scavello, Christopher P. Davie, Andrew J. Pope, David Holmes, Taylor L. Graham, Minghui Wang, John Martin, Keith Rafferty, Ghotas Evindar, Enoch N. Gao, Lluis Ballell, Hongfeng Deng, Alfonso Mendoza-Losana, Quinn Lu
The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

Publisher URL: https://www.nature.com/articles/ncomms16081

DOI: 10.1038/ncomms16081

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