Expanding the Binding Envelope of CYP51 Inhibitors Targeting Trypanosoma cruzi with 4‐Aminopyridyl‐Based Sulfonamide Derivatives |
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Authors: | Dr Debora F Vieira Dr Jun Yong Choi Prof Dr William R Roush Prof Dr Larissa M Podust |
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Affiliation: | 1. Department of Pathology, Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158 (USA);2. Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458 (USA) |
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Abstract: | Chagas disease is a chronic infection caused by the protozoan parasite Trypanosoma cruzi, manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Therapeutic options to prevent or treat Chagas disease are limited. CYP51, the enzyme key to the biosynthesis of eukaryotic membrane sterols, is a validated drug target in both fungi and T. cruzi. Sulfonamide derivatives of 4‐aminopyridyl‐based inhibitors of T. cruzi CYP51 (TcCYP51), including the sub‐nanomolar compound 3 , have molecular structures distinct from other validated CYP51 inhibitors. They augment the biologically relevant chemical space of molecules targeting TcCYP51. In a 2.08 Å X‐ray structure, TcCYP51 is in a conformation that has been influenced by compound 3 and is distinct from the previously characterized ground‐state conformation of CYP51 drug–target complexes. That the binding site was modulated in response to an incoming inhibitor for the first time characterizes TcCYP51 as a flexible target rather than a rigid template. |
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Keywords: | Chagas disease CYP51 drug design inhibitors protein structures |
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