Computational Approaches to Anesthetic Drug Discovery

McGrath, Megan; Pence, Andrea; Raines, Douglas E.

doi:10.1016/j.tips.2019.09.001

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…Understanding the mechanisms of action of general anesthetics at the molecular level is important [1][2][3][4][5][6]. It provides a basis for improving existing general anesthetics and developing new ones.…”

Section: Introductionmentioning

confidence: 99%

Anesthetic-Binding Induced Motion of GABA_AReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Nakata

Mori

Tanaka

2023

Preprint

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General anesthetics are indispensable in modern medicine because they induce a reversible loss of consciousness and sensation in humans. On the other hand, their molecular mechanisms of action have not yet been elucidated. Several studies have identified the main targets of some general anesthetics. The structures of gamma-aminobutyric acid A (GABA A) receptors with the intravenous anesthetics such as propofol and etomidate have recently been determined. Although these anesthetic-binding structures provide essential insights into the mechanism of action of anesthetics, the detailed molecular mechanism of how the anesthetic binding affects the Cl- permeability of GABA A receptors remains to be elucidated. In this study, we performed coarse-grained molecular dynamics simulations for GABA A receptors and analyzed the resulting simulation trajectories to investigate the effects of anesthetic binding on the motion of GABA A receptors. The results showed large structural fluctuations in GABA A receptors, correlations of motion between the amino-acid residues, large amplitude motion, and autocorrelated slow motion, which were obtained by advanced statistical analyses. In addition, comparison of the resulting trajectories in the presence or absence of the anesthetic molecules revealed a characteristic pore motion related to the gate-opening motion of GABA A receptors.

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Section: Introductionmentioning

confidence: 99%

Anesthetic-Binding Induced Motion of GABA_AReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Nakata

Mori

Tanaka

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Understanding the mechanisms of action of general anesthetics at the molecular level is important. − It provides a basis for improving existing general anesthetics and developing new ones. While several anesthetics have well-described mechanisms, the mechanisms of action of some general anesthetics remain unclear despite many years of research.…”

Section: Introductionmentioning

confidence: 99%

Anesthetic Binding Induced Motion of GABA_A Receptors Revealed by Coarse-Grained Molecular Dynamics Simulations

2023

View full text Add to dashboard Cite

General anesthetics are indispensable in modern medicine because they induce a reversible loss of consciousness and sensation in humans. On the other hand, their molecular mechanisms of action have not yet been elucidated. Several studies have identified the main targets of some general anesthetics. The structures of γ-aminobutyric acid A (GABA A ) receptors with the intravenous anesthetics such as propofol and etomidate have recently been determined. Although these anesthetic binding structures provide essential insights into the mechanism of action of anesthetics, the detailed molecular mechanism of how the anesthetic binding affects the Cl − permeability of GABA A receptors remains to be elucidated. In this study, we performed coarse-grained molecular dynamics simulations for GABA A receptors and analyzed the resulting simulation trajectories to investigate the effects of anesthetic binding on the motion of GABA A receptors. The results showed large structural fluctuations in GABA A receptors, correlations of motion between the amino acid residues, large amplitude motion, and autocorrelated slow motion, which were obtained by advanced statistical analyses. In addition, a comparison of the resulting trajectories in the presence or absence of the anesthetic molecules revealed a characteristic pore motion related to the gate-opening motion of GABA A receptors.

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Discovery of the EL-0052 as a potential anesthetic drug

Jiang

et al. 2021

Computational and Structural Biotechnology Journal

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Computational Approaches to Anesthetic Drug Discovery

Cited by 3 publications

References 10 publications

Anesthetic-Binding Induced Motion of GABA_AReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Anesthetic-Binding Induced Motion of GABA_AReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Anesthetic Binding Induced Motion of GABA_A Receptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Discovery of the EL-0052 as a potential anesthetic drug

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Computational Approaches to Anesthetic Drug Discovery

Cited by 3 publications

References 10 publications

Anesthetic-Binding Induced Motion of GABAAReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Anesthetic-Binding Induced Motion of GABAAReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Anesthetic Binding Induced Motion of GABAA Receptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Discovery of the EL-0052 as a potential anesthetic drug

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Product

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Anesthetic-Binding Induced Motion of GABA_AReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Anesthetic-Binding Induced Motion of GABA_AReceptors Revealed by Coarse-Grained Molecular Dynamics Simulations

Anesthetic Binding Induced Motion of GABA_A Receptors Revealed by Coarse-Grained Molecular Dynamics Simulations