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 b2-Adrenergic (b2AR) is a GPCR target for the treatment of asthma. Many of the drugs used to treat asthma show an increase in amplified mucus-production and tachyphylaxis, which actually worsen the symptoms of asthma. Therefore, new drugs targeting b2AR are required that differentially impact downstream signaling than current therapeutic agents, an outcome that may be achieved through compounds that stabilize alternate conformations of the protein. To achieve this the Climber approach combined with long time-scale molecular dynamics simulations have been applied to both active and inactive b2AR conformations to identify novel intermediate functional conformations as defined by the interhelical conformations. These conformations were further characterized using the SILCS methodology, including calculations of fragment occupancy maps, FragMaps, HotSpots analysis and pharmacophore modeling which were followed by virtual screening. Preliminary experimental analysis (cyclic AMP generation, protein kinase A activation and smooth muscle relaxation) of identified compounds show the approach to successfully yield new b2AR agonist that may be functioning via an allosteric mechanism.

Exploring the interhelical landscape of the β2 adrenergic receptor to identify new allosteric modulators using molecular dynamics and site identification by ligand competitive saturation (SILCS)

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.