Details

Autor(en) / Beteiligte

• Gong, Qijie
• Yu, Quanwei
• Wang, Nan
• Hu, Jiabao
• Wang, Pengfei
• Yang, Fulai
• Li, Tian
• You, Qidong
• Li, Xiang
• Zhang, Xiaojin

Titel

Application of cation-π interactions in enzyme-substrate binding: Design, synthesis, biological evaluation, and molecular dynamics insights of novel hydrophilic substrates for NQO1

Ist Teil von

• European journal of medicinal chemistry, 2021-10, Vol.221, p.113515-113515, Article 113515

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 × 106 M−1s−1, 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 (IC50/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. [Display omitted] •Tertiary amine groups improve water solubility and the NQO1-substrate binding through cation-π interactions.•The NQO1-substrate binding modes were analyzed by molecular dynamics simulation.•Compound 4 exerted good NQO1 targeting antitumor activity with improved druglike properties.