5opa | pdb_00005opa
The crystal structure of P450 CYP121 in complex with lead compound 7b
Structural highlights
Function[CP121_MYCTO] Catalyzes C-C bond formation between the carbons ortho to the phenolic hydroxyl of cyclo(L-tyr-L-tyr) (cYY) producing mycocyclosin. Can also use cyclo(L-Tyr-L-Phe) (cYF), cyclo(L-Tyr-L-Trp) (cYW) and cyclo(L-Tyr-L-3,4-dihydroxyphenylalanine) (cY-DOPA) as substrate (By similarity). Publication Abstract from PubMedThree 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 -CH2- linker displayed promising antimycobacterial activity, with the imidazole-CH2- series (7) showing low MIC values (6.25-25 mug/mL), which was also influenced by lipophilicity. Extending the linker to -C(O)NH(CH2)2- resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV-visible optical titrations with KD values of 2.63, 35.6, and 290 muM, 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. Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation.,Taban IM, Elshihawy HEAE, Torun B, Zucchini B, Williamson CJ, Altuwairigi D, Ngu AST, McLean KJ, Levy CW, Sood S, Marino LB, Munro AW, de Carvalho LPS, Simons C J Med Chem. 2017 Dec 28;60(24):10257-10267. doi: 10.1021/acs.jmedchem.7b01562., Epub 2017 Dec 7. PMID:29185746[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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