US EPA

7307801 

Journal Article 

Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength 

Samuels, ER; Sevrioukova, IF 

2021 

Yes 

International Journal of Molecular Sciences
ISSN: 1422-0067
EISSN: 14220067 

22 

2 

1-23 

English 

33467005 

10.3390/ijms22020852 

WOS:000611324000001 

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85099603339&doi=10.3390%2fijms22020852&partnerID=40&md5=2b0f77cdfe2f7b710f355d58bdd422d9
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Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug-drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure-activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R1/R2 side-groups as phenyls or R1-phenyl/R2-indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl-ethyl to pyridyl-propyl, was beneficial and markedly improved Ks, IC50 and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h, was among the best inhibitors designed so far and overall, the strongest binder (Ks and IC50 of 0.007 and 0.090 µM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach. 

Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 CYP3A; EC 1.14.14.1; CYP3A4 protein, human; EC 1.14.14.55; Ritonavir; O3J8G9O825; Index Medicus; crystal structure; inhibitor design; surface mutation; structure–activity relations; ligand binding; Drug Design; Protein Binding; Molecular Docking Simulation; Binding Sites; Quantitative Structure-Activity Relationship; Ritonavir -- analogs & derivatives; Cytochrome P-450 CYP3A -- chemistry; Cytochrome P-450 CYP3A -- metabolism; Cytochrome P-450 CYP3A Inhibitors -- pharmacology; Cytochrome P-450 CYP3A Inhibitors -- chemical synthesis