scholarly journals Distinct Binding Mechanisms for Allosteric Sodium Ion In Cannabinoid Receptors

2021 ◽  
Author(s):  
Soumajit Dutta ◽  
Balaji Selvam ◽  
Diwakar Shukla
Keyword(s):  
Free Energy ◽  
Binding Site ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Standard Free Energy ◽  
Allosteric Modulators ◽  
Dynamic Simulations ◽  
Markov State Models ◽  
State Models ◽  
Orthosteric Ligands

The therapeutical potential of Cannabinoid receptors is not fully explored due to psychoactive side-effects and lack of selectivity associated with the orthosteric ligands. Allosteric modulators have the potential to become selective therapeutics for cannabi- noid receptors. Biochemical experiments have shown the effects of the allosteric Na+ binding on cannabinoid receptor activity. However, the Na+ coordination site, and binding pathway are still unknown. Here, we perform molecular dynamic simulations to explore Na+ binding in the cannabinoid receptors, CB1 and CB2. Simulations reveal that Na+ binds to the primary binding site from different extracellular sites for CB1 and CB2. A distinct secondary Na+ coordinate site is identified that is not present in CB2. Furthermore, simulations also show that intracellular Na+ could bind to the Na+ binding site in CB1. Constructed Markov state models show that the standard free energy of Na+ binding is similar to the previously calculated free energy for other class A GPCRs.

scholarly journals Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery

2019 ◽  
Vol 11 (15) ◽  
pp. 2019-2037 ◽  
Author(s):  
Francesca Gado ◽  
Serena Meini ◽  
Simone Bertini ◽  
Maria Digiacomo ◽  
Marco Macchia ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Allosteric Modulators ◽  
Cb2 Receptor ◽  
Pharmacological Profile ◽  
Therapeutic Benefits ◽  
Structure Activity ◽  
Biased Signaling ◽  
Orthosteric Ligands

Allosteric modulators of cannabinoid receptors hold great therapeutic potential, as they do not possess intrinsic efficacy, but instead enhance or diminish the receptor's response of orthosteric ligands allowing for the tempering of cannabinoid receptor signaling without the desensitization, tolerance and dependence. Allosteric modulators of cannabinoid receptors have numerous advantages over the orthosteric ligands such as higher receptor type selectivity, probe dependence and biased signaling, so they have a great potential to separate the therapeutic benefits from side effects own of orthosteric ligands. This review aims to give an overview of the CB1 and CB2 receptor allosteric modulators highlighting the structure–activity relationship and pharmacological profile of each classes, and their future promise.

scholarly journals The histone H3 N-terminal tail: a computational analysis of the free energy landscape and kinetics

2015 ◽  
Vol 17 (20) ◽  
pp. 13689-13698 ◽  
Author(s):  
Yuqing Zheng ◽  
Qiang Cui
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Critical Role ◽  
Histone H3 ◽  
Free Energy Landscape ◽  
Chromatin Dynamics ◽  
Markov State Models ◽  
State Models ◽  
Dynamics Simulations ◽  
Kinetics Of

Extensive molecular dynamics simulations and Markov State models are used to characterize the free energy landscape and kinetics of the histone H3 N-terminal tail, which plays a critical role in regulating chromatin dynamics and gene activity.

scholarly journals In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 453
Author(s):  
Jiayi Yuan ◽  
Chen Jiang ◽  
Junmei Wang ◽  
Chih-Jung Chen ◽  
Yixuan Hao ◽  
...  
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Cannabinoid Receptors ◽  
Md Simulations ◽  
Docking Studies ◽  
Allosteric Modulators ◽  
3D Structures ◽  
Potential Binding ◽  
Allosteric Sites ◽  
Allosteric Binding Sites

Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-WIN 55,212-2 complex, among which sites B, C, G and K are supported by the reported 3D structures of Class A GPCRs coupled with AMs. Applying our novel algorithm toolset-MCCS, we docked three known AMs of CB2 including Ec2la (C-2), trans-β-caryophyllene (TBC) and cannabidiol (CBD) to each site for further comparisons and quantified the potential binding residues in each allosteric binding site. Sequentially, we selected the most promising binding pose of C-2 in five allosteric sites to conduct the molecular dynamics (MD) simulations. Based on the results of docking studies and MD simulations, we suggest that site H is the most promising allosteric binding site. We plan to conduct bio-assay validations in the future.

scholarly journals Extracellular Calcium Modulates Actions of Orthosteric and Allosteric Ligands on Metabotropic Glutamate Receptor 1α

2013 ◽  
Vol 289 (3) ◽  
pp. 1649-1661 ◽  
Author(s):  
Jason Y. Jiang ◽  
Mulpuri Nagaraju ◽  
Rebecca C. Meyer ◽  
Li Zhang ◽  
Donald Hamelberg ◽  
...  
Keyword(s):  
Binding Site ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Extracellular Domain ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Allosteric Modulators ◽  
Metabotropic Glutamate ◽  
Intracellular Ca ◽  
Orthosteric Ligands

Metabotropic glutamate receptor 1α (mGluR1α), a member of the family C G protein-coupled receptors, is emerging as a potential drug target for various disorders, including chronic neuronal degenerative diseases. In addition to being activated by glutamate, mGluR1α is also modulated by extracellular Ca2+. However, the underlying mechanism is unknown. Moreover, it has long been challenging to develop receptor-specific agonists due to homologies within the mGluR family, and the Ca2+-binding site(s) on mGluR1α may provide an opportunity for receptor-selective targeting by therapeutics. In the present study, we show that our previously predicted Ca2+-binding site in the hinge region of mGluR1α is adjacent to the site where orthosteric agonists and antagonists bind on the extracellular domain of the receptor. Moreover, we found that extracellular Ca2+ enhanced mGluR1α-mediated intracellular Ca2+ responses evoked by the orthosteric agonist l-quisqualate. Conversely, extracellular Ca2+ diminished the inhibitory effect of the mGluR1α orthosteric antagonist (S)-α-methyl-4-carboxyphenylglycine. In addition, selective positive (Ro 67-4853) and negative (7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester) allosteric modulators of mGluR1α potentiated and inhibited responses to extracellular Ca2+, respectively, in a manner similar to their effects on the response of mGluR1α to glutamate. Mutations at residues predicted to be involved in Ca2+ binding, including E325I, had significant effects on the modulation of responses to the orthosteric agonist l-quisqualate and the allosteric modulator Ro 67-4853 by extracellular Ca2+. These studies reveal that binding of extracellular Ca2+ to the predicted Ca2+-binding site in the extracellular domain of mGluR1α modulates not only glutamate-evoked signaling but also the actions of both orthosteric ligands and allosteric modulators on mGluR1α.

scholarly journals Cannabinoid receptor type-1: breaking the dogmas

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 990 ◽  
Author(s):  
Arnau Busquets Garcia ◽  
Edgar Soria-Gomez ◽  
Luigi Bellocchio ◽  
Giovanni Marsicano
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Cell Types ◽  
Allosteric Modulators ◽  
Receptor Field ◽  
Intracellular Compartments ◽  
Specific Localization ◽  
Brain Connections

The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.

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