Open AccessClobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5
Author(s) -
William C. Wright,
Jude Chenge,
Jingheng Wang,
Hazel M. Girvan,
Lei Yang,
Sergio C. Chai,
Andrew D. Huber,
Jing Wu,
Peter Oladimeji,
Andrew W. Munro,
Taosheng Chen
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b02067
Subject(s) - chemistry , cyp3a4 , clobetasol propionate , heme , cytochrome p450 , cyp3a5 , active site , enzyme , stereochemistry , biochemistry , pharmacology , biology , gene , immunology , genotype , psoriasis
The human cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 metabolize most drugs and have high similarities in their structure and substrate preference. Whereas CYP3A4 is predominantly expressed in the liver, CYP3A5 is upregulated in cancer, contributing to drug resistance. Selective inhibitors of CYP3A5 are, therefore, critical to validating it as a therapeutic target. Here we report clobetasol propionate (clobetasol) as a potent and selective CYP3A5 inhibitor identified by high-throughput screening using enzymatic and cell-based assays. Molecular dynamics simulations suggest a close proximity of clobetasol to the heme in CYP3A5 but not in CYP3A4. UV-visible spectroscopy and electron paramagnetic resonance analyses confirmed the formation of an inhibitory type I heme-clobetasol complex in CYP3A5 but not in CYP3A4, thus explaining the CYP3A5 selectivity of clobetasol. Our results provide a structural basis for selective CYP3A5 inhibition, along with mechanistic insights, and highlight clobetasol as an important chemical tool for target validation.