Construction, Activity Evaluation and Molecular Simulation Study of α-Naphthylthiol Amino Acid Esters as Novel LSD1 Inhibitors
10.13748/j.cnki.issn1007-7693.20220402
- VernacularTitle:新型α-萘巯基氨基酸乙酯类LSD1抑制剂的构建、活性评价与分子模拟研究
- Author:
Zhonghua LI
1
;
Zhenzhen WANG
1
;
Tingting QIN
1
;
Pan WANG
1
;
Kai HU
1
;
Zhishen XIE
1
;
Lixin LI
1
;
Xiaowei ZHANG
1
;
Junying SONG
1
;
Weihong REN
2
;
Jinlian MA
1
Author Information
1. Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, China
2. Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450046, China
- Publication Type:Journal Article
- Keywords:
novel lysine specific demethylase 1(LSD1);
inhibitors;
molecular docking;
dynamic simulation
- From:
Chinese Journal of Modern Applied Pharmacy
2024;41(3):295-302
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE :To design and synthesize novel α-naphthylthiol amino acid ester lysine specific demethylase 1(LSD1) inhibitors, evaluate their inhibitory activity with selectivity against LSD1, and explore their binding mechanism through molecular docking and dynamics simulation.
METHODS
Based on the binding mode of hit compound 3a with LSD1, the α- naphthyl mercapto amino acid ethyl ester small molecule compound were designed by fixing the planar hydrophobic naphthyl ring in the structure, while introducing hydrophilic amino fragment, and they were prepared through a multi-component one-pot cascade reaction. All the compounds were evaluated for their inhibitory activity against LSD1 at concentrations of 5.0 and 1.0 μmol·L–1 using the LSD1 screening platform of research group. The most potent compound was tested for its IC50 value and enzyme selectivity over MAO-A and MAO-B, and its binding mode was investigated through molecular docking and dynamics simulation.
RESULTS
A total of 13 compounds were obtained, all of which exhibited significant inhibitory effects on LSD1. Among them, nine compounds showed an inhibitory rate of over 50.0% against LSD1 at a concentration of 1.0 μmol·L–1, while compound 3l displaying the best activity with an IC50 value of 0.17 μmol·L–1, 174 times higher than the positive control. It also showed excellent selectivity towards MAO-A and MAO-B. Molecular docking and dynamics simulations indicated that compound 3l inhibited the activity of LSD1 through multiple interactions.
CONCLUSION
The structures of α-naphthylthiol amino acid ester can serve as lead compounds or active fragments, laying a solid foundation for the subsequent design of LSD1 inhibitors based on structure-oriented drug design.
