Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods
As a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT2A) receptor is known for its critical role in the cognitive, behavioural and physiological functions, and thus is a primary molecular target to treat psychiatric diseases, including especially depression. With purpose to explore the s...
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| Format: | Article |
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MDPI AG
2017-06-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/22/7/1064 |
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| author | Feng Lin Feng Li Chao Wang Jinghui Wang Yinfeng Yang Ling Yang Yan Li |
| author_facet | Feng Lin Feng Li Chao Wang Jinghui Wang Yinfeng Yang Ling Yang Yan Li |
| author_sort | Feng Lin |
| collection | DOAJ |
| description | As a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT2A) receptor is known for its critical role in the cognitive, behavioural and physiological functions, and thus is a primary molecular target to treat psychiatric diseases, including especially depression. With purpose to explore the structural traits affecting the inhibitory activity, currently a dataset of 109 arylpiperazine derivatives as promising 5-HT2A antagonists was built, based on which the ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) study by using both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches was carried out. The resultant optimal CoMSIA model displays proper validity and predictability with cross-validated correlation coefficient Q2 = 0.587, non-cross-validated correlation coefficient R2ncv = 0.900 and predicted correlation coefficient for the test set of compounds R2pre = 0.897, respectively. Besides, molecular docking was also conducted to investigate the binding mode between these ligands and the active site of the 5-HT2A receptor. Meanwhile, as a docking supplementary tool to study the antagonists’ conformation in the binding cavity, molecular dynamics (MD) simulation was also performed, providing further elucidation about the changes in the ligand-receptor complex. Lastly, some new molecules were also newly-designed based on the above results that are potential arylpiperazine antagonists of 5-HT2A receptor. We hope that the present models and derived information may be of help for facilitating the optimization and design of novel potent antagonists as antidepressant drugs as well as exploring the interaction mechanism of 5-HT2A antagonists. |
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| format | Article |
| id | doaj.art-6d131c33030c4b8a982d7f7daecb29b4 |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T21:46:56Z |
| publishDate | 2017-06-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6d131c33030c4b8a982d7f7daecb29b42022-12-21T19:25:40ZengMDPI AGMolecules1420-30492017-06-01227106410.3390/molecules22071064molecules22071064Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico MethodsFeng Lin0Feng Li1Chao Wang2Jinghui Wang3Yinfeng Yang4Ling Yang5Yan Li6Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Pharmacy School, Shihezi University, Shihezi 832002, Xinjiang, ChinaDepartment of Civil Engineering, Henan Institute of Engineering, Zhengzhou 451191, Henan, ChinaKey Laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, Liaoning, ChinaKey Laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, Liaoning, ChinaKey Laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, Liaoning, ChinaInstitute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaKey Laboratory of Xinjiang Endemic Phytomedicine Resources, Pharmacy School, Shihezi University, Shihezi 832002, Xinjiang, ChinaAs a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT2A) receptor is known for its critical role in the cognitive, behavioural and physiological functions, and thus is a primary molecular target to treat psychiatric diseases, including especially depression. With purpose to explore the structural traits affecting the inhibitory activity, currently a dataset of 109 arylpiperazine derivatives as promising 5-HT2A antagonists was built, based on which the ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) study by using both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches was carried out. The resultant optimal CoMSIA model displays proper validity and predictability with cross-validated correlation coefficient Q2 = 0.587, non-cross-validated correlation coefficient R2ncv = 0.900 and predicted correlation coefficient for the test set of compounds R2pre = 0.897, respectively. Besides, molecular docking was also conducted to investigate the binding mode between these ligands and the active site of the 5-HT2A receptor. Meanwhile, as a docking supplementary tool to study the antagonists’ conformation in the binding cavity, molecular dynamics (MD) simulation was also performed, providing further elucidation about the changes in the ligand-receptor complex. Lastly, some new molecules were also newly-designed based on the above results that are potential arylpiperazine antagonists of 5-HT2A receptor. We hope that the present models and derived information may be of help for facilitating the optimization and design of novel potent antagonists as antidepressant drugs as well as exploring the interaction mechanism of 5-HT2A antagonists.http://www.mdpi.com/1420-3049/22/7/1064depression5-HT2A receptorarylpiperazine derivative3D-QSARmolecular dockingmolecular dynamics |
| spellingShingle | Feng Lin Feng Li Chao Wang Jinghui Wang Yinfeng Yang Ling Yang Yan Li Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods Molecules depression 5-HT2A receptor arylpiperazine derivative 3D-QSAR molecular docking molecular dynamics |
| title | Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods |
| title_full | Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods |
| title_fullStr | Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods |
| title_full_unstemmed | Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods |
| title_short | Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods |
| title_sort | mechanism exploration of arylpiperazine derivatives targeting the 5 ht2a receptor by in silico methods |
| topic | depression 5-HT2A receptor arylpiperazine derivative 3D-QSAR molecular docking molecular dynamics |
| url | http://www.mdpi.com/1420-3049/22/7/1064 |
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