Structure activity relationship of 2-arylalkynyl-adenine derivatives as human A<sub>3</sub> adenosine receptor antagonists

Yu, Jinha; Mannes, Philip Z.; Jung, Young‐Hwan; Ciancetta, Antonella; Bitant, Amelia; Lieberman, David I; Khaznadar, Sami S.; Auchampach, John A.; Gao, Zhan‐Guo

doi:10.1039/c8md00317c

Cited by 6 publications

(3 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The binding affinities of all the final compounds 9a–l were evaluated, using radioligand binding assays at four human AR subtypes ( Table 1 ), by reported methods [ 20 ]. All of the final compounds 9a – l exhibited medium to high binding affinity at the hA 3 AR, while no binding affinity at other subtypes such as hA 1 , hA 2A , and hA 2B ARs was observed.…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Choi

Jeong

2021

Pharmaceuticals

Self Cite

View full text Add to dashboard Cite

A new series of 4′-selenoadenosine-5′-N,N-dimethyluronamide derivatives as highly potent and selective human A3 adenosine receptor (hA3AR) antagonists, is described. The highly selective A3AR agonists, 4′-selenoadenosine-5′-N-methyluronamides were successfully converted into selective antagonists by adding a second N-methyl group to the 5′-uronamide position. All the synthesized compounds showed medium to high binding affinity at the hA3AR. Among the synthesized compounds, 2-H-N6-3-iodobenzylamine derivative 9f exhibited the highest binding affinity at hA3AR. (Ki = 22.7 nM). The 2-H analogues generally showed better binding affinity than the 2-Cl analogues. The cAMP functional assay with 2-Cl-N6-3-iodobenzylamine derivative 9l demonstrated hA3AR antagonist activity. A molecular modelling study suggests an important role of the hydrogen of 5′-uronamide as an essential hydrogen bonding donor for hA3AR activation.

show abstract

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Choi

Jeong

2021

Pharmaceuticals

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the aforementioned study, the 2-arylethynyl moiety pointed toward the outwardly displaced TM2, as expected for 2-substituted nucleosides. However, an alternative binding mode was recently proposed for a series of 2-arylalkynyl-adenine hA 3 AR antagonists, where the lack of the ribose moiety enabled the compounds to occupy the orthosteric site upside down, with a bidentate H-bond between the key N250 6.55 and the adenine N3 and N9 positions, and the 2-arylalkynyl group hosted by a hydrophobic pocket between TM5 and TM6 [73]. Thus, the adenine moiety does not need to persist in the same orientation as in the nucleoside when the ribose or pseudoribose is absent.…”

Section: Postprocessing Of Molecular Docking Posesmentioning

confidence: 99%

In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors

Salmaso

2020

Biomolecules

Self Cite

View full text Add to dashboard Cite

Molecular modeling has contributed to drug discovery for purinergic GPCRs, including adenosine receptors (ARs) and P2Y receptors (P2YRs). Experimental structures and homology modeling have proven to be useful in understanding and predicting structure activity relationships (SAR) of agonists and antagonists. This review provides an excursus on molecular dynamics (MD) simulations applied to ARs and P2YRs. The binding modes of newly synthesized A1AR- and A3AR-selective nucleoside derivatives, potentially of use against depression and inflammation, respectively, have been predicted to recapitulate their SAR and the species dependence of A3AR affinity. P2Y12R and P2Y1R crystallographic structures, respectively, have provided a detailed understanding of the recognition of anti-inflammatory P2Y14R antagonists and a large group of allosteric and orthosteric antagonists of P2Y1R, an antithrombotic and neuroprotective target. MD of A2AAR (an anticancer and neuroprotective target), A3AR, and P2Y1R has identified microswitches that are putatively involved in receptor activation. The approach pathways of different ligands toward A2AAR and P2Y1R binding sites have also been explored. A1AR, A2AAR, and A3AR were utilizes to study allosteric phenomena, but locating the binding site of structurally diverse allosteric modulators, such as an A3AR enhancer LUF6000, is challenging. Ligand residence time, a predictor of in vivo efficacy, and the structural role of water were investigated through A2AAR MD simulations. Thus, new MD and other modeling algorithms have contributed to purinergic GPCR drug discovery.

show abstract

“…Current assessment of GPCR docking simulations without QM/MM showed that the success rate was over 70%. Docking error was evident especially for the docking of ZM241385 and XAC into Adenosine A 2A receptor [41,42]. In 2016, Kim and Cho incorporated QM and solvation effect into the docking simulation of GPCRs to improve the predicting accuracy.…”

Section: Molecular Docking Development Using Qm/mm Approachmentioning

confidence: 99%

Multiscale Molecular Modeling in G Protein-Coupled Receptor (GPCR)-Ligand Studies

et al. 2020

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are major drug targets due to their ability to facilitate signal transduction across cell membranes, a process that is vital for many physiological functions to occur. The development of computational technology provides modern tools that permit accurate studies of the structures and properties of large chemical systems, such as enzymes and GPCRs, at the molecular level. The advent of multiscale molecular modeling permits the implementation of multiple levels of theories on a system of interest, for instance, assigning chemically relevant regions to high quantum mechanics (QM) level of theory while treating the rest of the system using classical force field (molecular mechanics (MM) potential). Multiscale QM/MM molecular modeling have far-reaching applications in the rational design of GPCR drugs/ligands by affording precise ligand binding configurations through the consideration of conformational plasticity. This enables the identification of key binding site residues that could be targeted to manipulate GPCR function. This review will focus on recent applications of multiscale QM/MM molecular simulations in GPCR studies that could boost the efficiency of future structure-based drug design (SBDD) strategies.

show abstract

Structure activity relationship of 2-arylalkynyl-adenine derivatives as human A₃ adenosine receptor antagonists

Abstract: Adenines that incorporate known agonist affinity-enhancing substituents are A3AR-selective antagonists.

Cited by 6 publications

References 43 publications

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors

Multiscale Molecular Modeling in G Protein-Coupled Receptor (GPCR)-Ligand Studies

Contact Info

Product

Resources

About

Structure activity relationship of 2-arylalkynyl-adenine derivatives as human A3 adenosine receptor antagonists

Abstract: Adenines that incorporate known agonist affinity-enhancing substituents are A3AR-selective antagonists.

Cited by 6 publications

References 43 publications

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors

Multiscale Molecular Modeling in G Protein-Coupled Receptor (GPCR)-Ligand Studies

Contact Info

Product

Resources

About

Structure activity relationship of 2-arylalkynyl-adenine derivatives as human A₃ adenosine receptor antagonists