Insights from Molecular Dynamics Simulations for GPCR Drug Discovery

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. There is evidence that some ligands that bind to the GPCRs activate different downstream signaling pathways. G protein activation or -arrestin biased signaling involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. Molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators' interactions between receptors and ligands. Here, we highlight recent simulation studies and methods used to study biased G protein-coupled receptor signaling and their conformational dynamics. We also highlight applications of MD simulations to drug discovery.

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Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery

International Journal of Molecular Sciences ◽

10.3390/ijms20174237 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4237 ◽

Cited By ~ 3

Author(s):

Zou ◽

Ewalt ◽

Keyword(s):

Molecular Dynamics ◽

Drug Discovery ◽

G Protein ◽

Drug Targets ◽

Conformational Dynamics ◽

Md Simulations ◽

Data Bank ◽

G Protein Coupled Receptor ◽

Biased Signaling ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. Some ligands that bind to GPCRs activate different downstream signaling pathways. G protein activation, or -arrestin biased signaling, involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. -arrestin biased signaling has become a hot target for structure-based drug discovery. However, challenges include that there are few crystal structures available in the Protein Data Bank and that GPCRs are highly dynamic. Hence, molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators’ interactions with receptors and ligands. Here, we highlight recent MD simulation studies and enhanced sampling methods used to study biased G protein-coupled receptor signaling and their conformational dynamics as well as applications to drug discovery.

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Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor

Quarterly Reviews of Biophysics ◽

10.1017/s0033583515000153 ◽

2015 ◽

Vol 48 (4) ◽

pp. 479-487 ◽

Cited By ~ 83

Author(s):

Kalli Kappel ◽

Yinglong Miao ◽

J. Andrew McCammon

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Binding Site ◽

G Protein ◽

Partial Agonist ◽

Md Simulations ◽

G Protein Coupled Receptor ◽

Accelerated Molecular Dynamics ◽

Dynamics Simulations ◽

G Protein Coupled

AbstractElucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein–ligand binding, especially the drug recognition of GPCRs.

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Understanding G Protein-Coupled Receptor Allostery via Molecular Dynamics Simulations: Implications for Drug Discovery

Methods in Molecular Biology - Computational Drug Discovery and Design ◽

10.1007/978-1-4939-7756-7_23 ◽

2018 ◽

pp. 455-472 ◽

Cited By ~ 3

Author(s):

Shaherin Basith ◽

Yoonji Lee ◽

Sun Choi

Keyword(s):

Molecular Dynamics ◽

Drug Discovery ◽

Molecular Dynamics Simulations ◽

G Protein ◽

G Protein Coupled Receptor ◽

Dynamics Simulations ◽

G Protein Coupled

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Evolving cryo-EM structural approaches for GPCR drug discovery

10.1101/2021.01.11.426276 ◽

2021 ◽

Author(s):

Xin Zhang ◽

Rachel M. Johnson ◽

Ieva Drulyte ◽

Lingbo Yu ◽

Abhay Kotecha ◽

...

Keyword(s):

Drug Discovery ◽

G Protein ◽

Drug Targets ◽

Conformational Dynamics ◽

Binding Pocket ◽

Drug Binding ◽

Commercial Application ◽

Gs Protein ◽

G Protein Coupled ◽

Bound Drug

AbstractG protein-coupled receptors (GPCRs) are the largest class of cell surface drug targets. Advances in biochemical approaches for the stabilisation of GPCR:transducer complexes together with improvements in the technology and application of cryo-EM has recently opened up new possibilities for structure-assisted drug design of GPCR agonists. Nonetheless, limitations in the commercial application of some of these approaches, including the use of nanobody 35 (Nb35) for stabilisation of GPCR:Gs complexes, and the high cost of 300kV imaging have restricted broad application of cryo-EM in drug discovery. Here, using the PF 06882961-bound GLP-1R as exemplar, we validated formation of stable complexes with a modified Gs protein in the absence of Nb35 that had equivalent resolution in the drug binding pocket to complexes solved in the presence of Nb35, while the G protein displayed increased conformational dynamics. In parallel, we assessed the performance of 200kV versus 300kV image acquisition using a Falcon 4 or K3 direct electron detector. We show that with 300kV Krios, both bottom mounted Falcon 4 and energy filtered (25eV slit) Bio-Quantum K3 produced similar resolution. Moreover, the 200kV Glacios with bottom mounted Falcon 4 yielded a 3.2 Å map with clear density for bound drug and multiple structurally ordered waters. Our work paves the way for broader commercial application of cryo-EM for GPCR drug discovery.

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