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- W2912267336 abstract "G-protein-coupled receptors (GPCRs) transmit information into a large number of signaling pathways based on various extracellular stimuli making GPCRs one of the most sought-after pharmaceutical targets. Lately, structural studies have generated essential understanding of how distinctive receptor conformations can be of importance in triggering different signaling pathways. Hence, one can potentially identify and specifically target these different conformations in order to design biased agonists, directing an exact intracellular response. The β2-Adrenergic receptor (β2AR) is of special interest as it is a GPCR target used for treatment of asthma. Many of the drugs used currently have shown an increase in amplified mucus-production and tachyphylaxis. These side-effects ultimately worsen the symptoms of asthma. Therefore, it is of great importance to expand the knowledge of how intermediate conformations of β2AR can be exploited in order to develop new drugs. To gain a deeper understanding of the dynamics of intermediary functional conformations of the β2AR, and how this is associated with the interhelical motions of activation, we have applied conventional long time-scale molecular dynamics simulations to both agonist and antagonist bound β2AR at different known conformations. Additionally, enhanced sampling methods, such as targeted molecular dynamics, have been used where external forces were employed to transition the inactive conformation to the fully active state. Subsequently, all external forces are released, and we can monitor the relaxation path of returning to an ‘inactive-like’ conformation. From this relaxation path we identify novel and potentially druggable intermediate states that are being characterized with the Site Identification by Ligand Competitive Saturation (SILCS) approach." @default.
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- W2912267336 date "2019-02-01" @default.
- W2912267336 modified "2023-09-27" @default.
- W2912267336 title "Exploring the Interhelical Landscape of the β-2 Adrenergic Receptor to Identify Druggable Intermediate States using Enhanced-Sampling Molecular Dynamics and Site Identification by Ligand Competitive Saturation (SILCS)" @default.
- W2912267336 doi "https://doi.org/10.1016/j.bpj.2018.11.1130" @default.
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