Inna V Krieger, Subbarao Yalamanchili, Paige Dickson, Curtis A Engelhart, Matthew D Zimmerman, Jeremy Wood, Ethan Clary, Jasmine Nguyen, Natalie Thornton, Paolo A Centrella, Betty Chan, John W Cuozzo, Martin Gengenbacher, Marie-Aude Guié, John P Guilinger, Corey Bienstock, Hajnalka Hartl, Christopher D Hupp, Rachael Jetson, Takashi Satoh, John T S Yeoman, Ying Zhang, Veronique Dartois, Dirk Schnappinger, Anthony D Keefe, James C Sacchettini
DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme...
April 5, 2024: ACS Infectious Diseases