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

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

  • Eur J Med Chem. 2021 Oct 5:221:113515. doi: 10.1016/j.ejmech.2021.113515.
Qijie Gong 1,  Quanwei Yu 1,  Nan Wang 2,  Jiabao Hu 3,  Pengfei Wang 4,  Fulai Yang 3,  Tian Li 4,  Qidong You 5,  Xiang Li 6,  Xiaojin Zhang 7
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 211198, China; Department of Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota-Twin Cities, Minneapolis, MN, USA.
  • 3 Department of Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 4 Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing, 211198, China.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: youqd@163.com.
  • 6 Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: lixiang@cpu.edu.cn.
  • 7 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 211198, China; Department of Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zxj@cpu.edu.cn.
PMID: 33984806 DOI: 10.1016/j.ejmech.2021.113515
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 × 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.

Keywords

Cation-π interaction; Molecular dynamics; NQO1; ROS; β-lapachone.

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