A Thermodynamic Discrimination of Efficacy of GPCR Ligands using Absolute Binding Free Energy Calculations

Abstract

G-protein-coupled receptors (GPCRs) play fundamental roles in most physiological processes by modulating diverse signaling pathways and thus have become one of the most important drug targets. Based on the fact that a variety of the extracellular signals are mediated in a ligand-specific manner such as inverse agonist, neutral antagonist and agonist, quantitative characterization of the ligand efficacy is essential for rational design of selective modulators for GPCR targets. As experimental methods used for this purpose are time-, cost- and labor-intensive, computational tools, if they were systematically able to predict the efficacy of GPCR ligands, would make a big impact on GPCR drug design. To tackle this issue, in this study we apply free energy perturbation molecular dynamics (FEP/MD) simulations to calculating absolute ligand binding free energy for β2-adrenergic receptor (β2AR)/ligand systems. Based on the characterization of binding free energy change with respect to simulation time and free energy decomposition, we present that computationally measured thermodynamic properties can be used as promising descriptors for discriminating the efficacy of GPCR ligands. In addition, the simulation results also provide further insights into β2AR activation dynamics and ligand binding affinity.