Identification of allosteric sites and ligand-induced modulation in the dopamine receptor through large-scale alchemical mutation scan.

ABSTRACT: G protein coupled receptors, particularly class A GPCRs are arguably the most important class of membrane receptors and preferred targets for drug development. Despite extensive research on how ligands modulate the receptor response, discovering new, highly specific ligands remains challenging. However, finding residues outside the conserved microswitches that affect the active-inactive state equilibrium and are specific for a certain receptor, can be beneficial for the design of ligands with higher receptor selectivity. Focusing on the human dopamine receptor 2 (DRD2), we uncover crucial residues for the activation modulation using alchemical non-equilibrium free energy calculations. Our findings match with literature on activation microswitches and experimental studies, while also uncove

SUBMITTER: Schmidt L 

PROVIDER: S-EPMC12036339 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature