5W0C

Cytochrome P450 (CYP) 2C9 TCA007 Inhibitor Complex

Summary for 5W0C

• Entry DOI: 10.2210/pdb5w0c/pdb
• Descriptor: Cytochrome P450 2C9, PROTOPORPHYRIN IX CONTAINING FE, ethyl {2-[([1,3]thiazolo[4,5-c]pyridine-2-carbonyl)amino]thiophene-3-carbonyl}carbamate, ... (5 entities in total)
• Functional Keywords: inhibitor complex, p450 monooxygenase, cytochrome p450 2c9, cyp2c9, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 55407.88

Authors

Johnson, E.F.,Hsu, M.-H. (deposition date: 2017-05-30, release date: 2017-09-13, Last modification date: 2023-10-04)

Primary citation

Liu, R.,Lyu, X.,Batt, S.M.,Hsu, M.H.,Harbut, M.B.,Vilcheze, C.,Cheng, B.,Ajayi, K.,Yang, B.,Yang, Y.,Guo, H.,Lin, C.,Gan, F.,Wang, C.,Franzblau, S.G.,Jacobs, W.R.,Besra, G.S.,Johnson, E.F.,Petrassi, M.,Chatterjee, A.K.,Futterer, K.,Wang, F.
Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.
Angew. Chem. Int. Ed. Engl., 56:13011-13015, 2017

PubMed Abstract: Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

PubMed: 28815830
DOI: 10.1002/anie.201707324

Experimental method

X-RAY DIFFRACTION (2.001 Å)