Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation
Small-molecule modulators of neurotensin receptor 1 (NTSR1), a class A G-protein-coupled receptor (GPCR), has emerged as promising therapeutic agent for psychiatric disorders and cancer. Interestingly, a chemical group substitution in NTSR1 modulators can launch different types of downstream regulat...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/7/2000 |
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| author | Xun Lu Xinchao Shi Jigang Fan Mingyu Li Yuxiang Zhang Shaoyong Lu Guanghuan Xu Ziqiang Chen |
| author_facet | Xun Lu Xinchao Shi Jigang Fan Mingyu Li Yuxiang Zhang Shaoyong Lu Guanghuan Xu Ziqiang Chen |
| author_sort | Xun Lu |
| collection | DOAJ |
| description | Small-molecule modulators of neurotensin receptor 1 (NTSR1), a class A G-protein-coupled receptor (GPCR), has emerged as promising therapeutic agent for psychiatric disorders and cancer. Interestingly, a chemical group substitution in NTSR1 modulators can launch different types of downstream regulation, highlighting the significance of deciphering the internal fine-tuning mechanism. Here, we conducted a synergistic application of a Gaussian accelerated molecular dynamics simulation, a conventional molecular dynamics simulation, and Markov state models (MSM) to investigate the underlying mechanism of ‘driver chemical groups’ of modulators triggering inverse signaling. The results indicated that the flexibility of the leucine moiety in NTSR1 agonists contributes to the inward displacement of TM7 through a loosely coupled allosteric pathway, while the rigidity of the adamantane moiety in NTSR1 antagonists leads to unfavorable downward transduction of agonistic signaling. Furthermore, we found that R322<sup>6.54</sup>, Y319<sup>6.51</sup>, F353<sup>7.42</sup>, R148<sup>3.32</sup>, S356<sup>7.45</sup>, and S357<sup>7.46</sup> may play a key role in inducing the activation of NTSR1. Together, our findings not only highlight the ingenious signal transduction within class A GPCRs but also lay a foundation for the development of targeted drugs harboring different regulatory functions of NTSR1. |
| first_indexed | 2024-03-11T00:44:11Z |
| format | Article |
| id | doaj.art-b3a018037e094bb19ba459e453298509 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T00:44:11Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-b3a018037e094bb19ba459e4532985092023-11-18T20:56:47ZengMDPI AGPharmaceutics1999-49232023-07-01157200010.3390/pharmaceutics15072000Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics SimulationXun Lu0Xinchao Shi1Jigang Fan2Mingyu Li3Yuxiang Zhang4Shaoyong Lu5Guanghuan Xu6Ziqiang Chen7Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaMedicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaMedicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaMedicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaMedicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaMedicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of VIP Clinic, Changhai Hospital, Affiliated to Navy Medical University, Shanghai 200433, ChinaDepartment of Orthopedics, Changhai Hospital, Affiliated to Naval Medical University, Shanghai 200433, ChinaSmall-molecule modulators of neurotensin receptor 1 (NTSR1), a class A G-protein-coupled receptor (GPCR), has emerged as promising therapeutic agent for psychiatric disorders and cancer. Interestingly, a chemical group substitution in NTSR1 modulators can launch different types of downstream regulation, highlighting the significance of deciphering the internal fine-tuning mechanism. Here, we conducted a synergistic application of a Gaussian accelerated molecular dynamics simulation, a conventional molecular dynamics simulation, and Markov state models (MSM) to investigate the underlying mechanism of ‘driver chemical groups’ of modulators triggering inverse signaling. The results indicated that the flexibility of the leucine moiety in NTSR1 agonists contributes to the inward displacement of TM7 through a loosely coupled allosteric pathway, while the rigidity of the adamantane moiety in NTSR1 antagonists leads to unfavorable downward transduction of agonistic signaling. Furthermore, we found that R322<sup>6.54</sup>, Y319<sup>6.51</sup>, F353<sup>7.42</sup>, R148<sup>3.32</sup>, S356<sup>7.45</sup>, and S357<sup>7.46</sup> may play a key role in inducing the activation of NTSR1. Together, our findings not only highlight the ingenious signal transduction within class A GPCRs but also lay a foundation for the development of targeted drugs harboring different regulatory functions of NTSR1.https://www.mdpi.com/1999-4923/15/7/2000neurotensin receptor 1molecular dynamic simulationsignal transductionselective interaction |
| spellingShingle | Xun Lu Xinchao Shi Jigang Fan Mingyu Li Yuxiang Zhang Shaoyong Lu Guanghuan Xu Ziqiang Chen Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation Pharmaceutics neurotensin receptor 1 molecular dynamic simulation signal transduction selective interaction |
| title | Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation |
| title_full | Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation |
| title_fullStr | Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation |
| title_full_unstemmed | Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation |
| title_short | Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation |
| title_sort | mechanistic elucidation of activation deactivation signal transduction within neurotensin receptor 1 triggered by driver chemical groups of modulators a comparative molecular dynamics simulation |
| topic | neurotensin receptor 1 molecular dynamic simulation signal transduction selective interaction |
| url | https://www.mdpi.com/1999-4923/15/7/2000 |
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