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Molecular dynamics study on the behavior and binding mechanism of target protein Transgelin-2 with its agonist TSG12 for anti-asthma drug discovery

文献类型：期刊论文

作者Wu, Leyun1,2; Wang, Guangpu3; Zhou, Liping1,2; Mo, Mengxia3; Shi, Yulong1,2; Li, Bo1,2; Yin, Leimiao4; Zhao, Qiang2,5; Yang, Yongqing4; Wu, Chengkun3
刊名COMPUTERS IN BIOLOGY AND MEDICINE
出版日期2023-02-01
卷号153页码:7
关键词Pharmaceutical sciences Molecular dynamics simulation Free energy calculation Asthma Target protein Transgelin-2 Agonist
ISSN号0010-4825
DOI10.1016/j.compbiomed.2022.106515
通讯作者Wu, Chengkun(chengkun_wu@nudt.edu.cn) ; Xu, Zhijian(zjxu@simm.ac.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn)
英文摘要Transgelin-2 (TG2) is a novel promising therapeutic target for the treatment of asthma as it plays an important role in relaxing airway smooth muscles and reducing pulmonary resistance in asthma. The compound TSG12 is the only reported TG2 agonist with in vivo anti-asthma activity. However, the dynamic behavior and ligand binding sites of TG2 and its binding mechanism with TSG12 remain unclear. In this study, we performed 12.6 mu s molecular dynamics (MD) simulations for apo-TG2 and TG2-TSG12 complex, respectively. The results suggested that the apo-TG2 has 4 most populated conformations, and that its binding of the agonist could expand the conformation distribution space of the protein. The simulations revealed 3 potential binding sites in 3 most populated conformations, one of which is induced by the agonist binding. Free energy decomposition uncovered 8 important residues with contributions stronger than-1 kcal/mol. Computational alanine scanning for the important residues by 100 ns conventional MD simulation for each mutated TG2-TSG12 complexes demonstrated that E27, R49 and F52 are essential residues for the agonist binding. These results should be helpful to under -stand the dynamic behavior of TG2 and its binding mechanism with the agonist TSG12, which could provide some structural insights into the novel mechanism for anti-asthma drug development.
资助项目Natural Science Foundation[81872797] ; National Key R&D Program of China[2022YFA1004304] ; National Key R&D Program of China[2022YFA1004303] ; SIMM-SUTCM
WOS研究方向Life Sciences & Biomedicine - Other Topics ; Computer Science ; Engineering ; Mathematical & Computational Biology
语种英语
WOS记录号WOS:000918143800001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/303660]  
专题新药研究国家重点实验室
通讯作者Wu, Chengkun; Xu, Zhijian; Zhu, Weiliang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
3.Natl Univ Def Technol, Inst Quantum Informat & State Key Lab High Perform, Coll Comp Sci & Technol, Changsha 410073, Peoples R China
4.Shanghai Univ Tradit Chinese Med, Yueyang Hosp, Shanghai 200030, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Leyun,Wang, Guangpu,Zhou, Liping,et al. Molecular dynamics study on the behavior and binding mechanism of target protein Transgelin-2 with its agonist TSG12 for anti-asthma drug discovery[J]. COMPUTERS IN BIOLOGY AND MEDICINE,2023,153:7.
APA Wu, Leyun.,Wang, Guangpu.,Zhou, Liping.,Mo, Mengxia.,Shi, Yulong.,...&Zhu, Weiliang.(2023).Molecular dynamics study on the behavior and binding mechanism of target protein Transgelin-2 with its agonist TSG12 for anti-asthma drug discovery.COMPUTERS IN BIOLOGY AND MEDICINE,153,7.
MLA Wu, Leyun,et al."Molecular dynamics study on the behavior and binding mechanism of target protein Transgelin-2 with its agonist TSG12 for anti-asthma drug discovery".COMPUTERS IN BIOLOGY AND MEDICINE 153(2023):7.

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来源：上海药物研究所

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