New Insights into Key Determinants for Adenosine 1 Receptor Antagonists Selectivity Using Supervised Molecular Dynamics Simulations

Giovanni Bolcato; Maicol Bissaro; Giuseppe Deganutti; Mattia Sturlese; Stefano Moro

doi:10.3390/biom10050732

New Insights into Key Determinants for Adenosine 1 Receptor Antagonists Selectivity Using Supervised Molecular Dynamics Simulations

Giovanni Bolcato, Maicol Bissaro, Giuseppe Deganutti, Mattia Sturlese, Stefano Moro

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Abstract

Adenosine receptors (ARs), like many otherGprotein-coupledreceptors (GPCRs), are targets of primary interest indrug design. However, one of the main limits for the development of drugs for this class of GPCRs is the complex selectivity profile usually displayed by ligands. Numerous efforts have been madefor clarifying the selectivity of ARs, leading to the development of many ligand-based models. The structure of the AR subtype A1 (A1AR) has been recently solved, providing important structural insights. In the present work, we rationalized the selectivity profile of two selective A1AR and A2AAR antagonists, investigating their recognition trajectories obtained by Supervised Molecular Dynamics from an unbound state and monitoring the role of the water molecules in the binding site.

Original language	English
Article number	732
Number of pages	11
Journal	Biomolecules
Volume	10
Issue number	5
DOIs	https://doi.org/10.3390/biom10050732
Publication status	Published - 7 May 2020
Externally published	Yes

Bibliographical note

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Keywords

A AR
Adenosine receptors
Antagonist
GPCRs
Moleculardynamics (MD)
Selectivity
Supervised molecular dynamics (SuMD)

ASJC Scopus subject areas

Biochemistry
Molecular Biology

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10.3390/biom10050732Licence: CC BY

PublishedFinal published version, 6.46 MBLicence: CC BY

Cite this

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title = "New Insights into Key Determinants for Adenosine 1 Receptor Antagonists Selectivity Using Supervised Molecular Dynamics Simulations",

abstract = "Adenosine receptors (ARs), like many otherGprotein-coupledreceptors (GPCRs), are targets of primary interest indrug design. However, one of the main limits for the development of drugs for this class of GPCRs is the complex selectivity profile usually displayed by ligands. Numerous efforts have been madefor clarifying the selectivity of ARs, leading to the development of many ligand-based models. The structure of the AR subtype A1 (A1AR) has been recently solved, providing important structural insights. In the present work, we rationalized the selectivity profile of two selective A1AR and A2AAR antagonists, investigating their recognition trajectories obtained by Supervised Molecular Dynamics from an unbound state and monitoring the role of the water molecules in the binding site.",

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author = "Giovanni Bolcato and Maicol Bissaro and Giuseppe Deganutti and Mattia Sturlese and Stefano Moro",

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AU - Bolcato, Giovanni

AU - Bissaro, Maicol

AU - Deganutti, Giuseppe

AU - Sturlese, Mattia

AU - Moro, Stefano

N1 - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

PY - 2020/5/7

Y1 - 2020/5/7

N2 - Adenosine receptors (ARs), like many otherGprotein-coupledreceptors (GPCRs), are targets of primary interest indrug design. However, one of the main limits for the development of drugs for this class of GPCRs is the complex selectivity profile usually displayed by ligands. Numerous efforts have been madefor clarifying the selectivity of ARs, leading to the development of many ligand-based models. The structure of the AR subtype A1 (A1AR) has been recently solved, providing important structural insights. In the present work, we rationalized the selectivity profile of two selective A1AR and A2AAR antagonists, investigating their recognition trajectories obtained by Supervised Molecular Dynamics from an unbound state and monitoring the role of the water molecules in the binding site.

AB - Adenosine receptors (ARs), like many otherGprotein-coupledreceptors (GPCRs), are targets of primary interest indrug design. However, one of the main limits for the development of drugs for this class of GPCRs is the complex selectivity profile usually displayed by ligands. Numerous efforts have been madefor clarifying the selectivity of ARs, leading to the development of many ligand-based models. The structure of the AR subtype A1 (A1AR) has been recently solved, providing important structural insights. In the present work, we rationalized the selectivity profile of two selective A1AR and A2AAR antagonists, investigating their recognition trajectories obtained by Supervised Molecular Dynamics from an unbound state and monitoring the role of the water molecules in the binding site.

KW - A AR

KW - Adenosine receptors

KW - Antagonist

KW - GPCRs

KW - Moleculardynamics (MD)

KW - Selectivity

KW - Supervised molecular dynamics (SuMD)

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DO - 10.3390/biom10050732

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JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 5

M1 - 732

ER -

New Insights into Key Determinants for Adenosine 1 Receptor Antagonists Selectivity Using Supervised Molecular Dynamics Simulations

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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