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.
- 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: [email protected].
- 6. Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
- 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: [email protected].
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.