Design of Drug Efficacy Guided by Free Energy Simulations of the β₂‐Adrenoceptor

Abstract

G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if highresolution receptor structures are available. We performed molecular dynamics simulations of the β 2 adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets.

Is the functional response of a receptor determined by the thermodynamics of ligand binding?

“…Notably, the restraints ensured that the separation between agonists and antagonists was close to ΔΔG = 0, an outcome that had not been achieved by similar approaches in previous studies with tight restraints outside the binding pocket. 17,18 Overall, our protocol has proven effective in accurately separating agonists and antagonists.…”

“…Saleh et al compared the ligand binding free energy calculated via metadynamics on different states of the receptor to explain biased signaling of the β2-adrenoceptor. 16 An analogous version of this thermodynamic model for relative binding free energies has recently been used to design partial agonists for the same target 17 and for the adenosine receptor A2A. 18 Similarly, the docking scores of ligands in distinct conformational states were used as a proxy for the binding free energy to predict the functional responses of various ligands.…”