Search for β2 Adrenergic Receptor Ligands by Virtual Screening via Grid Computing and Investigation of Binding Modes by Docking and Molecular Dynamics Simulations

Bai, Qifeng; Shao, Yongliang; Pan, Dabo; Zhang, Yang; Liu, Huanxiang; Yao, Xiaojun

doi:10.1371/journal.pone.0107837

Cited by 14 publications

(5 citation statements)

References 74 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The order in which the ligands were stably bound to BSA was: Rhein > Emodin > Aloe-emodin > Chrysophanol > Physcion. Two independent molecular docking studies was done by Autodock 4.2 and CDOCKER (Bai et al, 2014;Abdel-Hamid et al, 2014;Akdogan et al, 2011;Kalathiya et al, 2014), were different for all the five ligands, but the hydrophobic force contribution had some common amino acid residues. The most common amino acid residue involved in the hydrophobic contacts, was an aromatic amino acid, Trp213.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Investigation of the interaction of anthraquinones of Cassia occidentalis seeds with bovine serum albumin by molecular docking and spectroscopic analysis: Correlation to their in vitro cytotoxic potential

Panigrahi

Suthar

Verma

et al. 2015

Food Research International

View full text Add to dashboard Cite

Section: Accepted Manuscriptmentioning

confidence: 99%

Investigation of the interaction of anthraquinones of Cassia occidentalis seeds with bovine serum albumin by molecular docking and spectroscopic analysis: Correlation to their in vitro cytotoxic potential

Panigrahi

Suthar

Verma

et al. 2015

Food Research International

View full text Add to dashboard Cite

“…In particular, simulation results show the role of critical residues and structural motifs responsible for transmitting allosteric signals from the agonist to the transducer-binding regions; TM3 and TM7 residues act as allosteric communication hubs in GRK/β-arrestin selective signaling, whereas TM5 residues favor G protein signaling. The residues and allosteric functional regions in β 2 AR, identified in the present study, can be targeted to design novel biased drugs, as information about functional hotspots in β-adrenergic receptors has been demonstrated to assist in delineating the mechanism of agonist-induced activation and biased signaling. ,,,,− …”

Section: Resultsmentioning

confidence: 92%

Biased Signaling in Mutated Variants of β₂-Adrenergic Receptor: Insights from Molecular Dynamics Simulations

Madhu,

Shewani,

Murarka

2024

J. Chem. Inf. Model.

View full text Add to dashboard Cite

The molecular basis of receptor bias in G proteincoupled receptors (GPCRs) caused by mutations that preferentially activate specific intracellular transducers over others remains poorly understood. Two experimentally identified biased variants of β 2 -adrenergic receptors (β 2 AR), a prototypical GPCR, are a triple mutant (T68F, Y132A, and Y219A) and a single mutant (Y219A); the former bias the receptor toward the β-arrestin pathway by disfavoring G protein engagement, while the latter induces G protein signaling explicitly due to selection against GPCR kinases (GRKs) that phosphorylate the receptor as a prerequisite of β-arrestin binding. Though rigorous characterizations have revealed functional implications of these mutations, the atomistic origin of the observed transducer selectivity is not clear. In this study, we investigated the allosteric mechanism of receptor bias in β 2 AR using microseconds of all-atom Gaussian accelerated molecular dynamics (GaMD) simulations. Our observations reveal distinct rearrangements in transmembrane helices, intracellular loop 3, and critical residues R131 3.50 and Y326 7.53 in the conserved motifs D(E)RY and NPxxY for the mutant receptors, leading to their specific transducer interactions. Moreover, partial dissociation of G protein from the receptor core is observed in the simulations of the triple mutant in contrast to the single mutant and wild-type receptor. The reorganization of allosteric communications from the extracellular agonist BI-167107 to the intracellular receptor−transducer interfaces drives the conformational rearrangements responsible for receptor bias in the single and triple mutants. The molecular insights into receptor bias of β 2 AR presented here could improve the understanding of biased signaling in GPCRs, potentially opening new avenues for designing novel therapeutics with fewer side-effects and superior efficacy.

show abstract

“…Bai et al [ 32 ] explored β2-AR ligands through virtual screening and MD simulation analysis. In the said study, the authors performed the virtual screening through MolGridCal and Autodock Vina (ADV) tools.…”

Section: Resultsmentioning

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

Search for β2 Adrenergic Receptor Ligands by Virtual Screening via Grid Computing and Investigation of Binding Modes by Docking and Molecular Dynamics Simulations

Cited by 14 publications

References 74 publications

Investigation of the interaction of anthraquinones of Cassia occidentalis seeds with bovine serum albumin by molecular docking and spectroscopic analysis: Correlation to their in vitro cytotoxic potential

Investigation of the interaction of anthraquinones of Cassia occidentalis seeds with bovine serum albumin by molecular docking and spectroscopic analysis: Correlation to their in vitro cytotoxic potential

Biased Signaling in Mutated Variants of β₂-Adrenergic Receptor: Insights from Molecular Dynamics Simulations

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

Contact Info

Product

Resources

About

Search for β2 Adrenergic Receptor Ligands by Virtual Screening via Grid Computing and Investigation of Binding Modes by Docking and Molecular Dynamics Simulations

Cited by 14 publications

References 74 publications

Investigation of the interaction of anthraquinones of Cassia occidentalis seeds with bovine serum albumin by molecular docking and spectroscopic analysis: Correlation to their in vitro cytotoxic potential

Investigation of the interaction of anthraquinones of Cassia occidentalis seeds with bovine serum albumin by molecular docking and spectroscopic analysis: Correlation to their in vitro cytotoxic potential

Biased Signaling in Mutated Variants of β2-Adrenergic Receptor: Insights from Molecular Dynamics Simulations

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

Contact Info

Product

Resources

About

Biased Signaling in Mutated Variants of β₂-Adrenergic Receptor: Insights from Molecular Dynamics Simulations