Molecular Basis of Ligand Dissociation from G Protein-Coupled Receptors and Predicting Residence Time
G protein-coupled receptors (GPCRs) are integral membrane proteins and represent the largest class of drug targets. During the past decades progress in structural biology has enabled the crystallographic elucidation of the architecture of these important macromolecules. It also provided atomic-level visualization of ligand-receptor interactions, dramatically boosting the impact of structure-based approaches in drug discovery. However, knowledge obtained through crystallography is limited to static structural information. Less information is available showing how a ligand associates with or dissociates from a given receptor, whose importance is in fact increasingly recognized by the drug research community. Owing to recent advances in computer power and algorithms, molecular dynamics stimulations have become feasible that help in analyzing the kinetics of the ligand binding process. Here, we review what is currently known about the dynamics of GPCRs in the context of ligand association and dissociation, as determined through both crystallography and computer simulations. We particularly focus on the molecular basis of ligand dissociation from GPCRs and provide case studies that predict ligand dissociation pathways and residence time.
Key wordsBinding kinetics Molecular dynamics simulations G protein-coupled receptor Dissociation rate Dissociation pathway
This research received support from the Innovative Medicines Initiative Joint Undertaking under K4DD (www.k4dd.eu), grant agreement no. 115366, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contribution. For more information, see www.imi.europa.eu. This study was further supported by National Natural Science Foundation of China (no. 81603170 to D.G.) and Natural Science Foundation of Jiangsu Province (no. BK20160234 to D.G.).
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