9COT

Crystal structure of CYP3A4 bound to an inhibitor

This is a non-PDB format compatible entry.

Summary for 9COT

• Entry DOI: 10.2210/pdb9cot/pdb
• Descriptor: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, (2R)-3-phenyl-2-{[(2S)-3-phenyl-2-(2,2,2-trifluoroacetamido)propyl]sulfanyl}-N-[3-(pyridin-3-yl)propyl]propanamide (3 entities in total)
• Functional Keywords: cytochrome p450, cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 56903.92

Authors

Sevrioukova, I.F. (deposition date: 2024-07-17, release date: 2025-01-08, Last modification date: 2025-03-05)

Primary citation

Samuels, E.R.,Sevrioukova, I.F.
Evaluation of Larger Side-Group Functionalities and the Side/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4.
Chem.Biol.Drug Des., 105:e70043-e70043, 2025

PubMed Abstract: A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R side-group and R end-group interplay when the R side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R/R-phenyl inhibitors upon elongation and/or fluorination of R-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R is pyridine, the impact of R-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration. Overall, the R-naphthalene/R-pyridine containing 2f (R/S) was the series lead compound and one of the strongest binders/inhibitors designed thus far (K = 0.009 μM; IC = 0.10 μM). Introduction of a larger biphenyl or fluorene as R did not lead to any improvements. Contrarily, fluorene-containing 13 was the series weakest binder and inhibitor (K = 0.734 μM; IC = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R-biphenyl, however, can switch positions with R-Boc to enable heme ligation. Thus, for small and chemically simple end-groups such as Boc and pyridine, the R/R interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.

PubMed: 39792691
DOI: 10.1111/cbdd.70043

Experimental method

X-RAY DIFFRACTION (2.81 Å)