4I4G: Crystal Structure Of Cyp3a4 Ligated To Oxazole-substituted Desoxyritonavir

Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.
PDB ID: 4I4GDownload
MMDB ID: 109397
PDB Deposition Date: 2012/11/27
Updated in MMDB: 2013/05
Experimental Method:
x-ray diffraction
Resolution: 2.72  Å
Source Organism:
Similar Structures:
Biological Unit for 4I4G: monomeric; determined by author
Molecular Components in 4I4G
Label Count Molecule
Protein (1 molecule)
Cytochrome P450 3A4(Gene symbol: CYP3A4)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB