GPUgrid New badge, new(ish) paper

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#1 GPUgrid New badge, new(ish) paper

Post by Newshound »


Dears,

we added a badge for a (not-so-recent-any-more) paper Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity. The abstract is here and the text is open-access.

It is interesting because it provides evidence about the kinetics (i.e., transient conformational changes) incurred by the µ-opioid receptor (MOR) upon binding to drugs. MOR is part of the large and important GPCR protein family, which is targeted by approx ~30% of the current drugs.

Abhijeet Kapoor, Gerard Martinez-Rosell, Davide Provasi, Gianni de Fabritiis & Marta Filizola
Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity
Scientific Reports volume 7, Article number: 11255 (2017)


While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a classical or G protein-biased opioid agonist, c) Identification of kinetically distinct conformational states to be used for the rational design of functionally selective ligands that may eventually be developed into improved drugs; d) Characterization of multiple activation/deactivation pathways of MOR, and e) Suggestion from calculated transition timescales that MOR conformational changes are not the rate-limiting step in receptor activation.


Source: http://www.gpugrid.net/forum_thread.php?id=4956
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