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Application of cation-π interactions in enzyme-substrate binding: Design, synthesis, biological evaluation, and molecular dynamics insights of novel hydrophilic substrates for NQO1.
- Source :
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European journal of medicinal chemistry [Eur J Med Chem] 2021 Oct 05; Vol. 221, pp. 113515. Date of Electronic Publication: 2021 May 06. - Publication Year :
- 2021
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Abstract
- Cation-π interaction is a type of noncovalent interaction formed between the π-electron system and the positively charged ion or moieties. In this study, we designed a series of novel NQO1 substrates by introducing aliphatic nitrogen-containing side chains to fit with the L-shaped pocket of NQO1 by the formation of cation-π interactions. Molecular dynamics (MD) simulation indicated that the basic N atom in the side chain of NQO1 substrates, which is prone to be protonated under physiological conditions, can form cation-π interactions with the Phe232 and Phe236 residues of the NQO1 enzyme. Compound 4 with a methylpiperazinyl substituent was identified as the most efficient substrate for NQO1 with the reduction rate and catalytic efficiency of 1263 ± 61 μmol NADPH/min/μmol NQO1 and 2.8 ± 0.3 × 10 <superscript>6</superscript>  M <superscript>-1</superscript> s <superscript>-1</superscript> , respectively. Notably, compound 4 exhibited increased water solubility (110 μg/mL) compared to that of β-lap (43 μg/mL), especially under acidic condition (pH = 3, solubility > 1000 μg/mL). Compound 4 (IC <subscript>50</subscript> /A549 = 2.4 ± 0.6 μM) showed potent antitumor activity against NQO1-rich cancer cells through ROS generation via NQO1-mediated redox cycling. These results emphasized that the application of cation-π interactions by introducing basic aliphatic amine moiety is beneficial for both the water solubility and the NQO1-substrate binding, leading to promising NQO1-targeting antitumor candidates with improved druglike properties.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Apoptosis drug effects
Binding Sites drug effects
Cations chemical synthesis
Cations chemistry
Cations pharmacology
Cell Survival drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Humans
Hydrophobic and Hydrophilic Interactions
Molecular Structure
NAD(P)H Dehydrogenase (Quinone) chemistry
NAD(P)H Dehydrogenase (Quinone) metabolism
Pyrazines chemical synthesis
Pyrazines chemistry
Structure-Activity Relationship
Substrate Specificity
Drug Design
Enzyme Inhibitors pharmacology
Molecular Dynamics Simulation
NAD(P)H Dehydrogenase (Quinone) antagonists & inhibitors
Pyrazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 221
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33984806
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113515