7UFE

Human CYP3A4 bound to an inhibitor

Summary for 7UFE

• Entry DOI: 10.2210/pdb7ufe/pdb
• Descriptor: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, GLYCEROL, ... (5 entities in total)
• Functional Keywords: cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 113869.88

Authors

Sevrioukova, I.F. (deposition date: 2022-03-22, release date: 2022-07-27, Last modification date: 2023-10-18)

Primary citation

Samuels, E.R.,Sevrioukova, I.F.
Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: Controlled inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) is utilized to boost bioavailability of anti-viral and immunosuppressant pharmaceuticals. We investigate structure-activity relationships (SARs) in analogues of ritonavir, a potent CYP3A4 inhibitor marketed as pharmacoenhancer, to determine structural elements required for potent inhibition and whether the inhibitory potency can be further improved via a rational structure-based design. This study investigated eight (series VI) inhibitors differing in head- and end-moieties and their respective linkers. SAR analysis revealed the multifactorial regulation of inhibitory strength, with steric constraints imposed on the tethered heme-ligating moiety being a key factor. Minimization of these constraints by changing the linkers' length/flexibility and N-heteroatom position strengthened heme coordination and markedly improved binding and/or inhibitory strength. Impact of the end-pyridine attachment was not uniform due to influence of other determinants controlling the ligand-binding mode. This interplay between pharmacophoric determinants and the end-group enlargement can be used for further inhibitor optimization.

PubMed: 35806297
DOI: 10.3390/ijms23137291

Experimental method

X-RAY DIFFRACTION (2.4 Å)