5OPA

The crystal structure of P450 CYP121 in complex with lead compound 7b

Summary for 5OPA

• Entry DOI: 10.2210/pdb5opa/pdb
• Descriptor: Mycocyclosin synthase, SULFATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: cytochrome p450 inhibitor complex, oxidoreductase
• Biological source: Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)
• Cellular location: Cytoplasm : P9WPP6
• Total number of polymer chains: 1
• Total formula weight: 44827.13

Authors

Levy, C.W. (deposition date: 2017-08-09, release date: 2018-03-28, Last modification date: 2024-05-01)

Primary citation

Taban, I.M.,Elshihawy, H.E.A.E.,Torun, B.,Zucchini, B.,Williamson, C.J.,Altuwairigi, D.,Ngu, A.S.T.,McLean, K.J.,Levy, C.W.,Sood, S.,Marino, L.B.,Munro, A.W.,de Carvalho, L.P.S.,Simons, C.
Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation.
J. Med. Chem., 60:10257-10267, 2017

PubMed Abstract: Three series of biarylpyrazole imidazole and triazoles are described, which vary in the linker between the biaryl pyrazole and imidazole/triazole group. The imidazole and triazole series with the short -CH- linker displayed promising antimycobacterial activity, with the imidazole-CH- series (7) showing low MIC values (6.25-25 μg/mL), which was also influenced by lipophilicity. Extending the linker to -C(O)NH(CH)- resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV-visible optical titrations with K values of 2.63, 35.6, and 290 μM, respectively, for the tightest binding compounds 7e, 8b, and 13d from their respective series. Both binding affinity assays and docking studies of the CYP121A1 inhibitors suggest type II indirect binding through interstitial water molecules, with key binding residues Thr77, Val78, Val82, Val83, Met86, Ser237, Gln385, and Arg386, comparable with the binding interactions observed with fluconazole and the natural substrate dicyclotyrosine.

PubMed: 29185746
DOI: 10.1021/acs.jmedchem.7b01562

Experimental method

X-RAY DIFFRACTION (1.345 Å)