7UFB
CYP3A4 bound to an inhibitor
Summary for 7UFB
| Entry DOI | 10.2210/pdb7ufb/pdb |
| Descriptor | Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, (2R)-3-phenyl-2-({(2S)-3-phenyl-2-[2-(pyridin-3-yl)acetamido]propyl}sulfanyl)-N-[(pyridin-3-yl)methyl]propanamide, ... (4 entities in total) |
| Functional Keywords | cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 56898.97 |
| Authors | Sevrioukova, I. (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 Cited by 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: 35806297DOI: 10.3390/ijms23137291 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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