7KS8

Crystal structure of human CYP3A4 with the caged inhibitor

Summary for 7KS8

• Entry DOI: 10.2210/pdb7ks8/pdb
• Descriptor: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 57414.54

Authors

Sevrioukova, I.S. (deposition date: 2020-11-21, release date: 2021-06-02, Last modification date: 2023-10-18)

Primary citation

Toupin, N.,Steinke, S.J.,Nadella, S.,Li, A.,Rohrabaugh Jr., T.N.,Samuels, E.R.,Turro, C.,Sevrioukova, I.F.,Kodanko, J.J.
Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4.
J.Am.Chem.Soc., 143:9191-9205, 2021

PubMed Abstract: We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, and : [Ru(tpy)(L)()]Cl (tpy = 2,2':6',2″-terpyridine) with L = 6,6'-dimethyl-2,2'-bipyridine (Mebpy; ), dimethylbenzo[]dipyrido[3,2-:2',3'-]phenazine (Medppn; ) and 3,6-dimethyl-10,15-diphenylbenzo[]dipyrido[3,2-:2',3'-]phenazine (MePhdppn; ), [Ru(tpy)(Mebpy)()]Cl () and [Ru(tpy)(Medppn)()]Cl (). Photochemical release of or from - was demonstrated, and the spectrophotometric evaluation of showed that it behaves similarly to free (type II heme ligation) after irradiation with visible light but not in the dark. Unexpectedly, the intact Ru(II) complexes and were found to inhibit CYP3A4 potently and specifically through direct binding to the active site without heme ligation. Caged inhibitors - showed dual action properties by combining photoactivated dissociation of or with efficient O production. In prostate adenocarcinoma DU-145 cells, compound had the best synergistic effect with vinblastine, the anticancer drug primarily metabolized by CYP3A4 . Thus, our study establishes a new paradigm in CYP inhibition using metalated complexes and suggests possible utilization of photoactive CYP3A4 inhibitory compounds in clinical applications, such as enhancement of therapeutic efficacy of anticancer drugs.

PubMed: 34110801
DOI: 10.1021/jacs.1c04155

Experimental method

X-RAY DIFFRACTION (2.5 Å)