Heterobivalent Ligand for the Adenosine A<sub>2A</sub>–Dopamine D<sub>2</sub> Receptor Heteromer

Pulido, Daniel; Casadó-Anguera, Verònica; Gómez-Autet, Marc; Llopart, Natàlia; Moreno, Estefanía; Casajuana-Martín, Nil; Ferré, Sergi; Pardo, Leonardo; Casadó, Vicent; Royo, Míriam

doi:10.1021/acs.jmedchem.1c01763

Cited by 19 publications

(14 citation statements)

References 67 publications

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“…Targeting A 2A R-D 2 R heteromers is a well-established therapeutic strategy for Parkinson's disease where A 2A R antagonism in conjunction with D 2 R agonism is highly desired. Commonly, A 2A R antagonists are dosed in conjunction with L-DOPA; however, there are continuing efforts to develop bivalent ligands to co-occupy and specifically target A 2A R-D 2 R heteromers [268][269][270]. Beyond A 2A R-D 2 R heteromers, multiple bona fide AR heteromeric complexes are of therapeutic interest and relevant in the setting of AD (Table 1).…”

Section: Therapeutic Potential Of Targeting Ar Oligomersmentioning

confidence: 99%

Adenosine receptor signalling in Alzheimer’s disease

Trinh

Baltos

Hellyer

et al. 2022

Purinergic Signalling

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Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer’s disease. The adenosine A1 and A2A receptors are expressed in the human brain and have a proposed involvement in the pathogenesis of dementia. Targeting these receptors preclinically can mitigate pathogenic β-amyloid and tau neurotoxicity whilst improving cognition and memory. In this review, we provide an accessible summary of the literature on Alzheimer’s disease and the therapeutic potential of A1 and A2A receptors. Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which may increase drug discovery success and enhance the therapeutic response.

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Section: Therapeutic Potential Of Targeting Ar Oligomersmentioning

confidence: 99%

Adenosine receptor signalling in Alzheimer’s disease

Trinh

Baltos

Hellyer

et al. 2022

Purinergic Signalling

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“…Remarkably, while the orthosteric binding site is conserved among family members, these sites at the ECDs are highly divergent and have become potential binding sites for synthetic modulators . Thus, they have been used in the design of allosteric modulators or bitopic ligands, , as well as proposed to bind short bivalent ligands. , …”

Section: Introductionmentioning

confidence: 99%

“…26 Thus, they have been used in the design of allosteric modulators 27 or bitopic ligands, 20,28 as well as proposed to bind short bivalent ligands. 29,30 Class A GPCRs activated by hormone-like signaling molecules derived from lipid species with long hydrophobic moieties 31 possess a distinctive structural signature at the ECD, in comparison with other class A GPCRs that are activated by polar ligands. 32 In the crystal structures of S1P 1 , 33 LPA1, 34 FFAR1, 35 CRTH2, 36 CB 1 , 37,38 and CB 2 39 receptors, the extracellular N-terminus and extracellular loop 2 fold over the ligand binding pocket.…”

Section: Introductionmentioning

confidence: 99%

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A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB₂ Receptor via the Lipid Bilayer

Casajuana-Martín

Navarro

González

et al. 2022

J. Chem. Inf. Model.

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Molecular dynamic (MD) simulations have become a common tool to study the pathway of ligand entry to the orthosteric binding site of G protein-coupled receptors. Here, we have combined MD simulations and site-directed mutagenesis to study the binding process of the potent JWH-133 agonist to the cannabinoid CB2 receptor (CB2R). In CB2R, the N-terminus and extracellular loop 2 fold over the ligand binding pocket, blocking access to the binding cavity from the extracellular environment. We, thus, hypothesized that the binding pathway is a multistage process consisting of the hydrophobic ligand diffusing in the lipid bilayer to contact a lipid-facing vestibule, from which the ligand enters an allosteric site inside the transmembrane bundle through a tunnel formed between TMs 1 and 7 and finally moving from the allosteric to the orthosteric binding cavity. This pathway was experimentally validated by the Ala2827.36Phe mutation that blocks the entrance of the ligand, as JWH-133 was not able to decrease the forskolin-induced cAMP levels in cells expressing the mutant receptor. This proposed ligand entry pathway defines transient binding sites that are potential cavities for the design of synthetic modulators.

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“…A 2A R activation reduces the binding affinity of D 2 R agonists, while A 2A R antagonists enhance the dopaminergic tone by decreasing the adenosine negative allosteric modulation on D 2 R. Heterobivalent ligands able to inhibit A 2A R and activate D 2 R represent a valuable pharmacological tool 36 and, in principle, therapeutic options for conditions characterized by reduction of dopaminergic signaling in the central nervous system. The successive dynamic docking of the heterobivalent ligand compound 26 37 to the heterodimer suggested by mwSuMD produced a ternary complex stabilized by lipids.…”

Section: Introductionmentioning

confidence: 99%

Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD)

Deganutti

Pipitò

Rujan

et al. 2022

Preprint

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G protein-coupled receptors (GPCRs) are the most abundant membrane proteins and the target of about 35% of approved drugs. Despite this, the structural basis of GPCR pharmacology is still a matter of intense study. Molecular dynamics (MD) simulations aim at expanding our knowledge of GPCR dynamics by building upon the recent advances in structural biology. However, the timescale limitations of classic MD hinder its applicability to numerous structural processes happening in time scales longer than microseconds (hidden structural transitions). For this reason, the overall MD impact on the study of GPCRs pharmacology and drug design is still limited. To overcome this, we have developed an unbiased adaptive sampling algorithm, namely multiple walker supervised MD (mwSuMD), and tested it on different hidden transitions involving GPCRs. By increasing the complexity of the simulated process, we report the binding and unbinding of the vasopressin peptide, the inactive-to-active transition of the glucagon-like peptide-1 receptor (GLP-1R), the stimulatory G protein (Gs) and inhibitory Gi binding to the adrenoreceptor β2 (β2 AR) and the adenosine 1 receptor (A1R) respectively, and the heterodimerization between the adenosine receptor A2 (A2AR) and the dopamine receptor D2 (D2R). We demonstrate that mwSuMD is a helpful tool for studying at the atomic level GPCR transitions that are challenging to address with classic MD simulations.

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Heterobivalent Ligand for the Adenosine A_2A–Dopamine D₂ Receptor Heteromer

Cited by 19 publications

References 67 publications

Adenosine receptor signalling in Alzheimer’s disease

Adenosine receptor signalling in Alzheimer’s disease

A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB₂ Receptor via the Lipid Bilayer

Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD)

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Heterobivalent Ligand for the Adenosine A2A–Dopamine D2 Receptor Heteromer

Cited by 19 publications

References 67 publications

Adenosine receptor signalling in Alzheimer’s disease

Adenosine receptor signalling in Alzheimer’s disease

A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB2 Receptor via the Lipid Bilayer

Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD)

Contact Info

Product

Resources

About

Heterobivalent Ligand for the Adenosine A_2A–Dopamine D₂ Receptor Heteromer

A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB₂ Receptor via the Lipid Bilayer