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The Dynamic Process of Drug–GPCR Binding at Either Orthosteric or Allosteric Sites Evaluated by Metadynamics

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Book cover G Protein-Coupled Receptors in Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1335))

Abstract

Major advances in G Protein-Coupled Receptor (GPCR) structural biology over the past few years have yielded a significant number of high-resolution crystal structures for several different receptor subtypes. This dramatic increase in GPCR structural information has underscored the use of automated docking algorithms for the discovery of novel ligands that can eventually be developed into improved therapeutics. However, these algorithms are often unable to discriminate between different, yet energetically similar, poses because of their relatively simple scoring functions. Here, we describe a metadynamics-based approach to study the dynamic process of ligand binding to/unbinding from GPCRs with a higher level of accuracy and yet satisfying efficiency.

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Acknowledgments

Funding for this work was provided by National Institutes of Health grants DA026434 and DA034049. Computations in the Filizola lab are performed on the Extreme Science and Engineering Discovery Environment (XSEDE) under MCB080109N, which is supported by National Science Foundation grant number OCI-1053575, and on the computational resources provided by the Scientific Computing Facility at the Icahn School of Medicine at Mount Sinai.

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  1. Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, P.O. Box 1677, New York, NY, 10029-6574, USA

    Sebastian Schneider, Davide Provasi & Marta Filizola

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  1. Sebastian Schneider
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  2. Davide Provasi
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  1. Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Marta Filizola

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Schneider, S., Provasi, D., Filizola, M. (2015). The Dynamic Process of Drug–GPCR Binding at Either Orthosteric or Allosteric Sites Evaluated by Metadynamics. In: Filizola, M. (eds) G Protein-Coupled Receptors in Drug Discovery. Methods in Molecular Biology, vol 1335. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2914-6_18

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  • DOI: https://doi.org/10.1007/978-1-4939-2914-6_18

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