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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Discovery of Multi-functional Lead Compounds Originating from Traditional Chinese Medicine for Developing Anti-depressive Agents via Virtual Screening

Author(s): Mo Jiajia, Xu Qinlong, Li Jiaming*, Chu Zhaoxing*, Ma Xiaodong, Zhu Qihua and He Guangwei

Volume 21, Issue 10, 2024

Published on: 08 May, 2023

Page: [1745 - 1754] Pages: 10

DOI: 10.2174/1570180820666230418104418

Price: $65

Abstract

Background: The increasing prevalence of depression has become a global health issue. Currently approved anti-depressive including 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), triple reuptake inhibitors (TRIs) and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists have limited effects because of their insufficient efficacy and/or slow onset of action. Developing multifunctional antidepressants that can modulate 5-HT, DA, NE, and NMDA simultaneously can potentially overcome the current drug defects.

Objective: This study aimed to explore leads for the development of multi-functional anti-depressive agents that simultaneous triple reuptake inhibitory and NMDA-GluN2B receptor antagonistic activities.

Methods: Potential leads were screened virtually from the TCMSP database based on the 3DPharmacophore model of TRIs followed by the molecular docking into NMDA-GluN2B receptor, BBB score, and the in silico toxicity evaluation. The biological activities of discovered leads on 5-HT, NE, and DA reuptake and their effect on the NMDA-GluN2B receptor were evaluated via radio-labeled neurotransmitters and competition radio-ligand binding experiment with [3H] ifenprodil, respectively. Lastly, the antidepressant effect of these potential leads was determined in vivo through the forced swim test in mice.

Results: Two compounds were attained as potential leads after the aforementioned experiments. Further in vitro biological evaluation identified Hit-2 as a promising lead that exerted favorable triple 5- HT/DA/NE reuptake inhibitory activity (66.98% inhibition rate at 10 μM against hNET, 73.01% inhibition rate at 1 μM against hDAT and 86.27% inhibition rate at 1 μM against hSERT), as well as potent NMDA-GluN2B receptor antagonistic activity (Ki=115.73 ± 3.54 nM). The antidepressant activity of Hit- 2 was confirmed through in vivo experiments

Conclusion: Hit-2 not only simultaneously inhibited the reuptake of 5-HT, DA, and NE, and acted as an NMDA-GluN2B receptor antagonist in vitro but also showed in vivo antidepressant activity. These findings may serve as a structural basis for the further development of multi-functional anti-depressive agents.

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