Development of covalent antagonists for β1- and β2-adrenergic receptors

Schwalbe, Tobias; Huebner, Harald; Gmeiner, Peter

doi:10.1016/j.bmc.2019.05.034

Cited by 7 publications

(5 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistently, CCK-8 results revealed that the two antagonists decreased the proliferation of glioma cells. Although the ADRBs can be divided into β1, β2, and β3 receptors, studies have reported that glioma tissues mainly express β1- and β2-adrenergic receptors ( 35 , 51 , 52 ). Therefore, the β1- and β2-receptors separately were further blocked.…”

Section: Discussionmentioning

confidence: 99%

Chronic stress promotes glioma cell proliferation via the PI3K/Akt signaling pathway

et al. 2021

View full text Add to dashboard Cite

High malignancy and high mortality of glioma render it urgent to elucidate the underlying mechanisms of glioma carcinogenesis and explore novel targets for therapy. Epidemiologic and clinical studies have revealed that chronic stress promotes the progression of various solid tumors and is correlated with poor prognosis; however, findings reporting the involvement of chronic stress in glioma are rare. In the present study, a chronic restraint animal model and a chronic stress cell model were established to explore the effects of chronic stress on glioma and its molecular mechanisms. The results revealed that chronic stress promoted glioma growth in vivo, and the serum levels of the stress hormones glucocorticoid (GC) and noradrenaline (NE) were significantly increased. In addition, GC and NE were verified to accelerate the proliferation of glioma cells in vitro. Mechanistically, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway was revealed to be activated under stress conditions, and inhibition of the expression of p-Akt could restrain the stress hormone-induced glioma cell proliferation. In addition, our data indicated that the GC receptor (GR) and β-adrenergic receptors (ADRBs) were both required for the biological functions of GC and NE in glioma cells. In conclusion, these results indicated that chronic stress and the stress hormones GC and NE activated PI3K/Akt signaling through binding to GR and ADRBs, thereby promoting glioma cell growth. Our findings may provide potential therapeutic targets and pave the way for the development of new strategies to protect patients with glioma from the detrimental effects of stress on tumor progression.

show abstract

Section: Discussionmentioning

confidence: 99%

Chronic stress promotes glioma cell proliferation via the PI3K/Akt signaling pathway

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Determination of washout resistance by radioligand binding is a frequently used method for the validation of a postulated irreversible interaction between a potential covalent ligand and the targeted receptor [15][16][17][18][19][20][21][22][23]. In this experimental design, the bound ligand 44 was washed out after the preincubation with hH 3 R expressing cell homogenate and showed a concentration-dependent labeling of the receptor, while the non-covalent control 42 and reference ligands recovered radioligand binding to vehicle levels.…”

Section: Discussionmentioning

confidence: 99%

“…In the field of kinases the use of TCIs has resulted in marketed drugs in past years [12], while the progress in covalent GPCR ligands is still limited in comparison [13]. Nonetheless, aided by advances in GPCR crystallography, covalent ligands targeting the orthosteric binding site of GPCRs have been disclosed [14][15][16][17][18][19][20][21][22][23]. The targeted GPCR residue is mostly a cysteine with diverse warheads being used, such as a disulfide [17,19,23], isothiocyanate [18], or Michael acceptor [15].…”

Section: Introductionmentioning

confidence: 99%

“…Nonetheless, aided by advances in GPCR crystallography, covalent ligands targeting the orthosteric binding site of GPCRs have been disclosed [14][15][16][17][18][19][20][21][22][23]. The targeted GPCR residue is mostly a cysteine with diverse warheads being used, such as a disulfide [17,19,23], isothiocyanate [18], or Michael acceptor [15]. Other residues have been targeted as well with various warheads, i.e., lysine with activated ester [16] or arylsulfonyl fluoride [20], tyrosine with an arylsulfonyl fluoride [22], or asparagine with an aziridinium ion [17].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Covalent Inhibition of the Histamine H3 Receptor

et al. 2019

View full text Add to dashboard Cite

Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H 3 receptor (H 3 R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H 3 R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H 3 R was validated with washout experiments and leads to inverse agonism on H 3 R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H 3 R conformation and to study the consequences of prolonged inhibition of the H 3 R.

show abstract

“…antagonists and inverse agonists (drugs that impede β1-AR and β2-AR signaling) are used to modify heart function. A number of research studies highlighted the identification of either agonist, partial agonists, or weak partial agonists of β-AR [ 11 , 17 , 18 , 19 , 20 , 21 , 22 ]. However, such investigation is facing a lot of challenges regarding the identification and development of selective β-blockers mainly because of allosteric factors and conformational flexibility [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Screening of β1- and β2-Adrenergic Receptor Modulators through Advanced Pharmacoinformatics and Machine Learning Approaches

Islam¹,

Rallabandi²,

Mohammed³

et al. 2021

IJMS

View full text Add to dashboard Cite

Cardiovascular diseases (CDs) are a major concern in the human race and one of the leading causes of death worldwide. β-Adrenergic receptors (β1-AR and β2-AR) play a crucial role in the overall regulation of cardiac function. In the present study, structure-based virtual screening, machine learning (ML), and a ligand-based similarity search were conducted for the PubChem database against both β1- and β2-AR. Initially, all docked molecules were screened using the threshold binding energy value. Molecules with a better binding affinity were further used for segregation as active and inactive through ML. The pharmacokinetic assessment was carried out on molecules retained in the above step. Further, similarity searching of the ChEMBL and DrugBank databases was performed. From detailed analysis of the above data, four compounds for each of β1- and β2-AR were found to be promising in nature. A number of critical ligand-binding amino acids formed potential hydrogen bonds and hydrophobic interactions. Finally, a molecular dynamics (MD) simulation study of each molecule bound with the respective target was performed. A number of parameters obtained from the MD simulation trajectories were calculated and substantiated the stability between the protein-ligand complex. Hence, it can be postulated that the final molecules might be crucial for CDs subjected to experimental validation.

show abstract

Development of covalent antagonists for β1- and β2-adrenergic receptors

Cited by 7 publications

References 50 publications

Chronic stress promotes glioma cell proliferation via the PI3K/Akt signaling pathway

Chronic stress promotes glioma cell proliferation via the PI3K/Akt signaling pathway

Covalent Inhibition of the Histamine H3 Receptor

Screening of β1- and β2-Adrenergic Receptor Modulators through Advanced Pharmacoinformatics and Machine Learning Approaches

Contact Info

Product

Resources

About