Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors

Dutta, Soumajit; Shukla, Diwakar

doi:10.1038/s42003-023-04868-1

Cited by 9 publications

(9 citation statements)

References 103 publications

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“…In cases where multiple conformations exist for the same activation state of the receptor (LUF5833 example in Figure D), sampling could be improved by using multiple active structures or multiple inactive structures, respectively, for the same target if available. As we gain more understanding of how receptors’ conformational ensembles influence the details of ligand efficacy, , we anticipate that our method can be applied to resolve distinct substates of the active macrostate and thus to classify the different activation pathways in a similar fashion as we have shown for the distinction between agonism and antagonism.…”

Section: Discussionmentioning

confidence: 93%

Is the Functional Response of a Receptor Determined by the Thermodynamics of Ligand Binding?

Vögele,

Zhang,

Kaindl

et al. 2023

J. Chem. Theory Comput.

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For an effective drug, strong binding to the target protein is a prerequisite, but it is not enough. To produce a particular functional response, drugs need to either block the proteins' functions or modulate their activities by changing their conformational equilibrium. The binding free energy of a compound to its target is routinely calculated, but the timescales for the protein conformational changes are prohibitively long to be efficiently modeled via physics-based simulations. Thermodynamic principles suggest that the binding free energies of the ligands with different receptor conformations may infer their efficacy. However, this hypothesis has not been thoroughly validated. We present an actionable protocol and a comprehensive study to show that binding thermodynamics provides a strong predictor of the efficacy of a ligand. We apply the absolute binding free energy perturbation method to ligands bound to active and inactive states of eight G protein-coupled receptors and a nuclear receptor and then compare the resulting binding free energies. We find that carefully designed restraints are often necessary to efficiently model the corresponding conformational ensembles for each state. Our method achieves unprecedented performance in classifying ligands as agonists or antagonists across the various investigated receptors, all of which are important drug targets.

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Section: Discussionmentioning

confidence: 93%

Is the Functional Response of a Receptor Determined by the Thermodynamics of Ligand Binding?

Vögele,

Zhang,

Kaindl

et al. 2023

J. Chem. Theory Comput.

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“…53 The following steps are taken for the practical implementation of the MSM from the MD data. 4,17,95–97…”

Section: Methodsmentioning

confidence: 99%

“…The following steps are taken for the practical implementation of the MSM from the MD data. 4,17,[95][96][97] 1. Each frame obtained from the MD simulation was featurized using features important for capturing the conformational ensemble.…”

Section: Markov State Modelmentioning

confidence: 99%

“…Quantitative values of the activation metrics for both active structures are compared as scatter points on 1-D line with the CB 1 inactive structure (PDB ID: 5TGZ, 1 color: orange). These quantitative measurements were discussed in Dutta and Shukla 4…”

Section: Introductionmentioning

confidence: 98%

“…Cannabinoid receptor 1 (CB 1 ), which is majorly expressed in the central nervous system (CNS) belongs to the class A G-protein coupled receptor (GPCR) family proteins. [1][2][3][4] GPCRs are expressed in the cellular membrane and help transduce chemical signals from the extracellular to the intracellular direction with the help of the downstream signaling proteins (G-proteins and β-arrestin). [5][6][7] In addition, GPCRs are the largest family of drug targets due to their substantial involvement in human pathophysiology and druggability.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method

Dutta,

Shukla

2023

Preprint

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New psychoactive substances (NPS) targeting cannabinoid receptor 1 (CB1) pose a significant threat to society as recreational abusive drugs that can avoid detection and have higher physiological side effects. These physiological side effects of NPS are shown to be linked to the higherβ-arrestin signaling. We hypothesize that the difference in conformational dynamics of the NPxxY motif causes the distinct downstream signaling of NPS contrary to the classical cannabinoids. To compare the dynamic effects of the NPS and classical cannabinoid binding on the NPxxY conformational ensemble, we simulate (un)binding process of NPS MDMB-Fubinaca and classical cannabinoid HU-210 from CB1using unbiased and biased molecular dynamics simulations. The transition-based reweighing method (TRAM) is used to combine multi-ensemble simulations for the estimation of transition rates and underlying thermodynamics of (un)binding processes of ligands with nanomolar affinities, where it is more expensive to obtain local reversible sampling. Our analyses suggest that the ligands unbind from the receptors using the same pathway but by a different mechanism. Further analyses reveal higher conformational fluctuation in the NPxxY motif for NPS bound CB1, supporting our hypothesis. The observation is further validated using a Variational autoencoder (VAE) based on Neural rational inference, which shows higher dynamic allostery-based interactions between the binding pocket residues and NPxxY for NPS bound CB1. Hence, in this work, MD simulation, data-driven statistical methods, and deep learning point out the significant differences in (un)binding and downstream signaling of NPS and classical cannabinoids.

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Cyclopamine modulates smoothened receptor activity in a binding position dependent manner

Kim,

Bansal,

Shukla

2024

Commun Biol

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Cyclopamine, a natural alkaloid, can act as an agonist when it binds to the Cysteine-Rich Domain (CRD) of Smoothened receptor and as an antagonist when it binds to the Transmembrane Domain (TMD). To study the effect of cyclopamine binding to each site experimentally, mutations in the other site are required. Hence, simulations are critical for understanding the WT activity due to binding at different sites. Using multi-milliseconds long aggregate MD simulations combined with Markov state models and machine learning, we explore the dynamic behavior of cyclopamine’s interactions with different domains of WT SMO. A higher population of the active state at equilibrium, a lower free energy barrier of ~2 kcal/mol, and expansion of hydrophobic tunnel to facilitate cholesterol transport agrees with cyclopamine’s agonistic behavior when bound to CRD. A higher population of the inactive state at equilibrium, a higher free energy barrier of ~4 kcal/mol and restricted hydrophobic tunnel shows cyclopamine’s antagonistic behavior when bound to TMD. With cyclopamine bound to both sites, there is a slightly larger inactive population at equilibrium and an increased free energy barrier (~3.5 kcal/mol) exhibiting an overall weak antagonistic effect. These findings show cyclopamine’s domain-specific modulation of SMO regulates Hedgehog signaling and cholesterol transport.

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Distinct activation mechanisms regulate subtype selectivity of Cannabinoid receptors

Cited by 9 publications

References 103 publications

Is the Functional Response of a Receptor Determined by the Thermodynamics of Ligand Binding?

Is the Functional Response of a Receptor Determined by the Thermodynamics of Ligand Binding?

Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method

Cyclopamine modulates smoothened receptor activity in a binding position dependent manner

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