Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation

Xun Lu
# ORCID logo ,
Xinchao Shi
# ORCID logo ,
Jigang Fan
,
Mingyu Li
,
Yuxiang Zhang
,
Shaoyong Lu
* ,
Guanhuan Xu
* ,
Ziqiang Chen
*
#
These authors contributed equally to the work.
Version 1 : Received: 30 June 2023 / Approved: 30 June 2023 / Online: 30 June 2023 (10:36:29 CEST)

A peer-reviewed article of this Preprint also exists.

Lu, X.; Shi, X.; Fan, J.; Li, M.; Zhang, Y.; Lu, S.; Xu, G.; Chen, Z. Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation. Pharmaceutics 2023, 15, 2000. Lu, X.; Shi, X.; Fan, J.; Li, M.; Zhang, Y.; Lu, S.; Xu, G.; Chen, Z. Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation. Pharmaceutics 2023, 15, 2000.

Abstract

Small molecule modulators of neurotensin receptor 1 (NTSR1), a class A G protein-coupled receptor (GPCR), has been emerging as promising therapeutics for psychiatric disorders and cancer. Interestingly, a chemical group substitution of NTSR1 modulators can launch different downstream regulation, highlighting the significance of deciphering the internal fine-tuning mechanism. Here, we conducted synergistic application of Gaussian accelerated molecular dynamics simulation, conventional molecular dynamics simulation, and Markov state models (MSM) to investigate the underpinning mechanism of ‘driver chemical groups’ of modulators triggering inverse signaling. The result indicated that the flexibility of leucine moiety in NTSR1 agonists contributes to the inward displacement of TM7 through a loosely coupled allosteric pathway, while the rigidity of adamantane moiety in NTSR1 antagonists leads to unfavorable downward transduction of agonistic signaling. Furthermore, we found that R3226.54, Y3196.51, F3537.42, R1483.32, S3567.45 and S3577.46 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 function of NTSR1.

Keywords

Neurotensin receptor 1; molecular dynamic simulation; signal transduction; selective interaction

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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