6UNG

Human CYP3A4 bound to an inhibitor

Summary for 6UNG

• Entry DOI: 10.2210/pdb6ung/pdb
• Related: 6UNE
• Descriptor: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, tert-butyl [(2S)-1-(naphthalen-1-yl)-3-{[(2R)-3-oxo-2-(phenylamino)-3-{[(pyridin-3-yl)methyl]amino}propyl]sulfanyl}propan-2-yl]carbamate, ... (4 entities in total)
• Functional Keywords: cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 56945.04

Authors

Sevrioukova, I.F. (deposition date: 2019-10-11, release date: 2020-02-05, Last modification date: 2023-10-11)

Primary citation

Samuels, 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

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)