6DAJ

Human CYP3A4 bound to an inhibitor

Summary for 6DAJ

• Entry DOI: 10.2210/pdb6daj/pdb
• Descriptor: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, tert-butyl [(2S)-1-{[(2R)-1-oxo-3-phenyl-1-{[2-(pyridin-3-yl)ethyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate, ... (5 entities in total)
• Functional Keywords: oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 57132.23

Authors

Sevrioukova, I.F. (deposition date: 2018-05-01, release date: 2019-04-03, Last modification date: 2023-10-04)

Primary citation

Samuels, E.R.,Sevrioukova, I.
Structure-Activity Relationships of Rationally Designed Ritonavir Analogues: Impact of Side-Group Stereochemistry, Headgroup Spacing, and Backbone Composition on the Interaction with CYP3A4.
Biochemistry, 58:2077-2087, 2019

PubMed Abstract: In a continuing effort to identify structural attributes required for strong binding and potent inhibition of human drug-metabolizing CYP3A4, we designed ten ritonavir-like analogues differing in the side-group stereochemistry, backbone atomic composition, and headgroup spacing. All analogues had pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating head and tail groups, respectively, phenyl side groups, and either a methyl- or ethyl-pyridyl linker. Each linker subseries had S/ R, R/ S, R/ R, and S/S side-group conformers (4a-d and 4e-h, respectively), and one S/S stereoisomer with the backbone S-to-N-heteroatom substitution (6a and 6b). To elucidate structure-activity relationships, ligand-dependent changes in optical spectra, dissociation constant ( K), inhibitory potency (IC), thermostability, and heme ligation and reduction kinetics were analyzed. Comparison of the subseries and individual compounds showed that CYP3A4 only weakly discriminates between side-group configurations, associates more tightly with the pyridyl-ethyl-linker analogues, and strongly disfavors the N-containing backbone. K and IC for the pyridyl-ethyl R/ R conformer, 4g, were the lowest and close to those for ritonavir: 0.04 and 0.31 μM versus 0.02 and 0.13 μM, respectively. Determination of the X-ray structures of the inhibitory complexes was critical for experimental data interpretation, especially for the uniquely oriented 4a and 4e. Based on structural analysis, we conclude that, for this series of analogues, the ligand-mediated interactions near the heme are dominant and define the binding mode and that fine-tuning of these interactions as well as the backbone spacing could further improve the affinity and inhibitory strength.

PubMed: 30912932
DOI: 10.1021/acs.biochem.9b00156

Experimental method

X-RAY DIFFRACTION (2.45 Å)