Citation: . Identification of Novel GABA_A Receptor Positive Allosteric Modulators with Novel Scaffolds via Multistep Virtual Screening[J]. Acta Physico-Chimica Sinica, ;2024, 40(1): 230204. doi: 10.3866/PKU.WHXB202302044 shu

Identification of Novel GABA_A Receptor Positive Allosteric Modulators with Novel Scaffolds via Multistep Virtual Screening

Received Date: 24 February 2023
Revised Date: 18 April 2023
Accepted Date: 19 April 2023
Available Online: 25 April 2023

The GABA_A receptor mainly mediates inhibitory signal transmission in mammalian central nervous systems and is the key target of sedative-hypnotics. However, the long-term use of sedative-hypnotics often leads to drug resistance, necessitating the development of novel sedative-hypnotics. This development can be achieved with novel scaffolds designed via the computer-aided drug design methods to obtain significant advantages. In this study, robust virtual screening models were established by identifying effective positive allosteric modulators of the GABA_A receptor from ChEMBL and BindingDB databases. These compounds combined with randomly extracted negative compounds were firstly applied for a 10-fold cross validation and grid search to establish machine learning models which were subsequently evaluated in an independent test set. In this step, 4 machine learning methods and 6 fingerprints were used to establish 24 models. In the test set, the CDK_LR model performed the best (MCC = 0.751) and was used for subsequent virtual screening. Two effective molecular docking models were also established based on conformation 6D6T and 6D6U, wherein the root mean square deviation (RMSD) values of redocking experiments were 1.141 and 1.505 Å (1 Å = 0.1 nm), respectively. During the virtual screening, 41112 compounds from a commercial database were scanned by machine learning, molecular docking, and molecular mechanics-generalized Born surface area models. After the screening, 16 hits were obtained, 4 of which were structurally novel positive hits verified by whole-cell patch-clamp electrophysiology experiments. The compound GPR120 was verified experimentally at both the cell and animal levels. In cortical neurons recombinantly expressing α1β2γ2-type receptors, at 10 and 50 µmol∙L⁻¹, GPR120 could potentiate GABA EC_3-10 current by 71.5% and 163.8%, respectively. Total decomposition contribution analysis and point mutation experiment showed that the key binding site between GPR120 and the GABA_A receptor is H102, similar to that of the positive drug Diazepam. To further verify GPR120 function at the animal level, locomotor activity and loss of righting reflex (LORR) tests were performed. GPR120 inhibited the locomotor activity of mice, which recovered after 6 h, indicating that GPR120 is a moderate sedative. In the pentobarbital sodium-induced righting reflex hour test, GPR120 (20 mg∙kg⁻¹) significantly shortened the time to start LORR and prolonged its duration compared with the saline control group. In summary, using integrated virtual screening methods, GPR120 was identified as a moderate sedative with a novel scaffold.
1. [1]
  Guanyang Zeng , Xingqiang Liu , Liangqiao Wu , Zijie Meng , Debin Zeng , Changlin Yu . Novel visible-light-driven I- doped Bi2O2CO3 nano-sheets fabricated via an ion exchange route for dye and phenol removal. Chinese Journal of Structural Chemistry, 2024, 43(12): 100462-100462. doi: 10.1016/j.cjsc.2024.100462
2. [2]
  Erzhuo Cheng , Yunyi Li , Wei Yuan , Wei Gong , Yanjun Cai , Yuan Gu , Yong Jiang , Yu Chen , Jingxi Zhang , Guangquan Mo , Bin Yang . Galvanostatic method assembled ZIFs nanostructure as novel nanozyme for the glucose oxidation and biosensing. Chinese Chemical Letters, 2024, 35(9): 109386-. doi: 10.1016/j.cclet.2023.109386
3. [3]
  Shaoqing Du , Xinyong Liu , Xueping Hu , Peng Zhan . Targeting novel sites represents an effective strategy for combating drug resistance. Chinese Chemical Letters, 2025, 36(1): 110378-. doi: 10.1016/j.cclet.2024.110378
4. [4]
  You Zhou , Li-Sheng Wang , Shuang-Gui Lei , Bo-Cheng Tang , Zhi-Cheng Yu , Xing Li , Yan-Dong Wu , Kai-Lu Zheng , An-Xin Wu . I₂-DMSO mediated tetra-functionalization of enaminones for the construction of novel furo[2′,3′:4,5]pyrimido[1,2-b]indazole skeletons via in situ capture of ketenimine cations. Chinese Chemical Letters, 2025, 36(1): 109799-. doi: 10.1016/j.cclet.2024.109799
5. [5]
  Qingyun Hu , Wei Wang , Junyuan Lu , He Zhu , Qi Liu , Yang Ren , Hong Wang , Jian Hui . High-throughput screening of high energy density LiMn_1-xFe_xPO₄ via active learning. Chinese Chemical Letters, 2025, 36(2): 110344-. doi: 10.1016/j.cclet.2024.110344
6. [6]
  Wu-Jian Long , Yang Yu , Chuang He . A novel and promising engineering application of carbon dots: Enhancing the chloride binding performance of cement. Chinese Chemical Letters, 2024, 35(6): 108943-. doi: 10.1016/j.cclet.2023.108943
7. [7]
  Ting-Ting Huang , Jin-Fa Chen , Juan Liu , Tai-Bao Wei , Hong Yao , Bingbing Shi , Qi Lin . A novel fused bi-macrocyclic host for sensitive detection of Cr₂O₇²⁻ based on enrichment effect. Chinese Chemical Letters, 2024, 35(7): 109281-. doi: 10.1016/j.cclet.2023.109281
8. [8]
  Tiantian Li , Ruochen Jin , Bin Wu , Dongming Lan , Yunjian Ma , Yonghua Wang . A novel insight of enhancing the hydrogen peroxide tolerance of unspecific peroxygenase from Daldinia caldariorum based on structure. Chinese Chemical Letters, 2024, 35(4): 108701-. doi: 10.1016/j.cclet.2023.108701
9. [9]
  Sinong Wang , Shanshan Jin , Xue Yang , Yanyan Huang , Peng Liu , Yi Tang , Yuliang Yang . Development of Mg-Al LDH and LDO as novel protective materials for deacidification of paper-based relics. Chinese Chemical Letters, 2024, 35(9): 109890-. doi: 10.1016/j.cclet.2024.109890
10. [10]
  Liping Zhao , Xixi Guo , Zhimeng Zhang , Xi Lu , Qingxuan Zeng , Tianyun Fan , Xintong Zhang , Fenbei Chen , Mengyi Xu , Min Yuan , Zhenjun Li , Jiandong Jiang , Jing Pang , Xuefu You , Yanxiang Wang , Danqing Song . Novel berberine derivatives as adjuvants in the battle against Acinetobacter baumannii: A promising strategy for combating multi-drug resistance. Chinese Chemical Letters, 2024, 35(10): 109506-. doi: 10.1016/j.cclet.2024.109506
11. [11]
  Deli Chen , Jiawen Li , Xudong Xu , Zhaocui Sun , Yun Yang , Minghui Xu , Hanqiao Liang , Junshan Yang , Hui Meng , Guoxu Ma , Jianhe Wei . Plant-microbial interactions inspired the discovery of novel sesquiterpenoid dimeric skeletons of hidden natural products from Hibiscus tiliaceus. Chinese Chemical Letters, 2024, 35(10): 109451-. doi: 10.1016/j.cclet.2023.109451
12. [12]
  Ran Wu , Dongxu Jiang , Hao Hu , Chenyu Yang , Liang Qin , Lulu Chen , Zehui Hu , Hualei Xu , Jinrong Li , Haiqiang Liu , Hua Guo , Jinxiang Fu , Qichen Hao , Yijun Zhou , Jinchao Feng , Qiang Wang , Xiaodong Wang . 4-Aminoazobenzene: A novel negative ion matrix for enhanced MALDI tissue imaging of metabolites. Chinese Chemical Letters, 2024, 35(11): 109624-. doi: 10.1016/j.cclet.2024.109624
13. [13]
  Yongjian Li , Xinyu Zhu , Chenxi Wei , Youyou Fang , Xinyu Wang , Yizhi Zhai , Wenlong Kang , Lai Chen , Duanyun Cao , Meng Wang , Yun Lu , Qing Huang , Yuefeng Su , Hong Yuan , Ning Li , Feng Wu . Unraveling the chemical and structural evolution of novel Li-rich layered/rocksalt intergrown cathode for Li-ion batteries. Chinese Chemical Letters, 2024, 35(12): 109536-. doi: 10.1016/j.cclet.2024.109536
14. [14]
  Zhiqing Ge , Zuxiong Pan , Shuo Yan , Baoying Zhang , Xiangyu Shen , Mozhen Wang , Xuewu Ge . Novel high-temperature thermochromic polydiacetylene material and its application as thermal indicator. Chinese Chemical Letters, 2024, 35(11): 109850-. doi: 10.1016/j.cclet.2024.109850
15. [15]
  Ran Cen , Yan-Yan Tang , Li-Xia Chen , Zhu Tao , Xin Xiao . A novel supramolecular assembly based on nor-seco-cucurbit[10]uril for spermine sensing and artificial light-harvesting. Chinese Chemical Letters, 2025, 36(1): 109744-. doi: 10.1016/j.cclet.2024.109744
16. [16]
  Meiling Xu , Xinyang Li , Pengyuan Liu , Junjun Liu , Xiao Han , Guodong Chai , Shuangling Zhong , Bai Yang , Liying Cui . A novel and visible ratiometric fluorescence determination of carbaryl based on red emissive carbon dots by a solvent-free method. Chinese Chemical Letters, 2025, 36(2): 109860-. doi: 10.1016/j.cclet.2024.109860
17. [17]
  Fan Zheng , Runsha Xiao , Shuai Huang , Zhikang Chen , Chen Lai , Anyao Bi , Heying Yao , Xueping Feng , Zihua Chen , Wenbin Zeng . Accurate visualization colorectal cancer by monitoring viscosity variations with a novel mitochondria-targeted fluorescent probe. Chinese Chemical Letters, 2025, 36(2): 109876-. doi: 10.1016/j.cclet.2024.109876
18. [18]
  Dongsheng Yang , Zixin Li , Yaoyao Lian , Ziyao Fu , Tianjiao Li , Pengtao Ma , Guoping Yang . A novel square-shaped Zr-substituted polyoxotungstate for the efficient catalytic oxidation of sulfide to sulfone. Chinese Chemical Letters, 2025, 36(3): 109717-. doi: 10.1016/j.cclet.2024.109717
19. [19]
  Hejie Zheng , Zhili Wang , Guizhen Luo , Cuicui Du , Xiaohua Zhang , Jinhua Chen . A novel PEC-EC dual-mode biosensing platform for dual target detection of miRNA-133a and cTnI. Chinese Chemical Letters, 2025, 36(4): 110131-. doi: 10.1016/j.cclet.2024.110131
20. [20]
  Hongyuan Sha , Dongling Yang , Yanran Shang , Zujian Wang , Rongbing Su , Chao He , Xiaoming Yang , Xifa Long . Trithionic guanidine: A novel semi-organic short-wave ultraviolet nonlinear optical sulfate with dimeric heteroleptic tetrahedra. Chinese Chemical Letters, 2025, 36(4): 109730-. doi: 10.1016/j.cclet.2024.109730

Get Citation

PDF

XML

Metrics

PDF Downloads(27)
Abstract views(1527)
HTML views(216)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Identification of Novel GABAA Receptor Positive Allosteric Modulators with Novel Scaffolds via Multistep Virtual Screening

Metrics

通讯作者: 陈斌, bchen63@163.com

Identification of Novel GABA_A Receptor Positive Allosteric Modulators with Novel Scaffolds via Multistep Virtual Screening