Loading
PDBj
MenuPDBj@FacebookPDBj@X(formerly Twitter)PDBj@BlueSkyPDBj@YouTubewwPDB FoundationwwPDB
RCSB PDBPDBeBMRBAdv. SearchSearch help

6UNI

Human CYP3A4 bound to an inhibitor

Summary for 6UNI
Entry DOI10.2210/pdb6uni/pdb
Related6UNE 6UNG 6UNH
DescriptorCytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, tert-butyl [(2S)-1-(1H-indol-3-yl)-3-{[(2R)-1-oxo-3-phenyl-1-{[2-(pyridin-3-yl)ethyl]amino}propan-2-yl]sulfanyl}propan-2-yl]carbamate (3 entities in total)
Functional Keywordscyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
Biological sourceHomo sapiens (Human)
Total number of polymer chains1
Total formula weight56933.03
Authors
Sevrioukova, I.F. (deposition date: 2019-10-11, release date: 2020-02-05, Last modification date: 2023-10-11)
Primary citationSamuels, E.R.,Sevrioukova, I.F.
An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.
Bioorg.Med.Chem., 28:115349-115349, 2020
Cited by
PubMed Abstract: Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R side-group as phenyl or naphthalene and R as indole or naphthalene in different stereo configuration showed that (i) analogues with the R-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R/R configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC of 0.055-0.085 μM vs. 0.130 μM, respectively).
PubMed: 32044230
DOI: 10.1016/j.bmc.2020.115349
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.602 Å)
Structure validation

227344

PDB entries from 2024-11-13

PDB statisticsPDBj update infoContact PDBjnumon