Journal article

Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.

Carmen Klein Herenbrink, Ravi Verma, Herman D Lim, Anitha Kopinathan, Alastair Keen, Jeremy Shonberg, Christopher J Draper-Joyce, Peter J Scammells, Arthur Christopoulos, Jonathan A Javitch, Ben Capuano, Lei Shi, J Robert Lane

ACS Chemical Biology | Published : 2019


Partial agonists of the dopamine D2 receptor (D2R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis, analytical pharmacology, ligand fragments, and molecular dynamics simulations to identify the D2R-aripiprazole interactions that contribute to affinity and efficacy. We reveal that an interaction between the secondary ph..

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