Format

Send to

Choose Destination
Sci Rep. 2017 Sep 12;7(1):11255. doi: 10.1038/s41598-017-11483-8.

Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity.

Author information

1
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C Dr Aiguader 88, Barcelona, 08003, Spain.
3
Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C Dr Aiguader 88, Barcelona, 08003, Spain. gianni.defabritiis@upf.edu.
4
Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys 23, Barcelona, 08010, Spain. gianni.defabritiis@upf.edu.
5
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. marta.filizola@mssm.edu.

Abstract

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center