Pathway and Mechanism of Drug Binding to Chemokine Receptors Revealed By Accelerated Molecular Simulations

Pawnikar, Shristi; Miao, Yinglong

doi:10.4155/fmc-2020-0044

Cited by 27 publications

(33 citation statements)

References 43 publications

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“…GaMD has been demonstrated on enhanced sampling and free energy calculations of ligand binding ( Miao et al, 2015 ; Pang et al, 2017 ), protein folding ( Miao et al, 2015 ; Pang et al, 2017 ), GPCR activation ( Miao and McCammon, 2016 ), and protein–membrane ( Bhattarai et al, 2020 ), protein–protein ( Miao and McCammon, 2018 ; Wang and Miao, 2019 ), and protein–nucleic acid ( Ricci et al, 2019 ; East et al, 2020 ) interactions. Of relevance to studies of GPCRs, GaMD simulations have successfully revealed the mechanisms of GPCR activation, ligand binding, and GPCR–G-protein interactions, which were consistent with experimental data and/or long timescale conventional MD (cMD) simulations ( Miao and McCammon, 2016 , Miao et al, 2018 ; Pawnikar and Miao, 2020 ).…”

Section: Introductionsupporting

confidence: 64%

“…It was located at the extracellular mouth between ECL2 and TM1 of the A 2A AR. This region has been identified as an allosteric site of many class A GPCRs ( Dror et al, 2013 ; Kruse et al, 2013 ; Miao and McCammon, 2016 ; Miao et al, 2018 ; Pawnikar and Miao, 2020 ). Taken together, our simulations suggest that CFF binds to the orthosteric pocket of A 2A AR via an intermediate site located at the receptor extracellular mouth.…”

Section: Discussionmentioning

confidence: 99%

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Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor

Hung

Akhter

Miao

2021

Front. Mol. Biosci.

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Caffeine (CFF) is a common antagonist to the four subtypes of adenosine G-protein-coupled receptors (GPCRs), which are critical drug targets for treating heart failure, cancer, and neurological diseases. However, the pathways and mechanism of CFF binding to the target receptors remain unclear. In this study, we have performed all-atom-enhanced sampling simulations using a robust Gaussian-accelerated molecular dynamics (GaMD) method to elucidate the binding mechanism of CFF to human adenosine A2A receptor (A2AAR). Multiple 500–1,000 ns GaMD simulations captured both binding and dissociation of CFF in the A2AAR. The GaMD-predicted binding poses of CFF were highly consistent with the x-ray crystal conformations with a characteristic hydrogen bond formed between CFF and residue N6.55 in the receptor. In addition, a low-energy intermediate binding conformation was revealed for CFF at the receptor extracellular mouth between ECL2 and TM1. While the ligand-binding pathways of the A2AAR were found similar to those of other class A GPCRs identified from previous studies, the ECL2 with high sequence divergence serves as an attractive target site for designing allosteric modulators as selective drugs of the A2AAR.

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Section: Introductionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor

Hung

Akhter

Miao

2021

Front. Mol. Biosci.

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“…Many research articles were published in Future Medicinal Chemistry last year that continue to be popular among our readers. Highlights include 'Pathway and mechanism of drug binding to chemokine receptors revealed by accelerated molecular simulations,' '3-amino-alkylated indoles: unexplored green products acting as anti-inflammatory agents' and 'Radiolabeling of [11C]FPS-ZM1, a receptor for advanced glycation end products-targeting positron emission tomography radiotracer, using a [11C]CO2-to-[11C]CO chemical conversion' [6][7][8].…”

Section: Content Highlights Of 2020mentioning

confidence: 99%

Welcome to Volume 13 of Future Medicinal Chemistry

Wall

2020

Future Med. Chem.

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“…Moreover, because the boost potential exhibits a Gaussian distribution, biomolecular free energy profiles can be properly recovered through cumulant expansion to the second order [ 23 ]. GaMD simulations have successfully revealed mechanisms of protein folding and conformational changes [ 23 , 25 , 26 , 27 , 28 , 29 ], ligand binding [ 23 , 26 , 27 , 30 , 31 , 32 , 33 , 34 , 35 ], and protein-protein/membrane/nucleic acid interactions [ 32 , 36 , 37 , 38 , 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

Conrad

Söldner

Miao

et al. 2020

IJMS

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The histamine H2 receptor (H2R) plays an important role in the regulation of gastric acid secretion. Therefore, it is a main drug target for the treatment of gastroesophageal reflux or peptic ulcer disease. However, there is as of yet no 3D-structural information available hampering a mechanistic understanding of H2R. Therefore, we created a model of the histamine-H2R-Gs complex based on the structure of the ternary complex of the β2-adrenoceptor and investigated the conformational stability of this active GPCR conformation. Since the physiologically relevant motions with respect to ligand binding and conformational changes of GPCRs can only partly be assessed on the timescale of conventional MD (cMD) simulations, we also applied metadynamics and Gaussian accelerated molecular dynamics (GaMD) simulations. A multiple walker metadynamics simulation in combination with cMD was applied for the determination of the histamine binding mode. The preferential binding pose detected is in good agreement with previous data from site directed mutagenesis and provides a basis for rational ligand design. Inspection of the H2R-Gs interface reveals a network of polar interactions that may contribute to H2R coupling selectivity. The cMD and GaMD simulations demonstrate that the active conformation is retained on a μs-timescale in the ternary histamine-H2R-Gs complex and in a truncated complex that contains only Gs helix α5 instead of the entire G protein. In contrast, histamine alone is unable to stabilize the active conformation, which is in line with previous studies of other GPCRs.

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Pathway and Mechanism of Drug Binding to Chemokine Receptors Revealed By Accelerated Molecular Simulations

Cited by 27 publications

References 43 publications

Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor

Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor

Welcome to Volume 13 of Future Medicinal Chemistry

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

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