Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole

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

Abstract

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 pharmacophore of aripiprazole and a secondary binding pocket defined by residues at the extracellular portions of transmembrane segments 1, 2 and 7 determine the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism through which to fine-tune the intrinsic efficacy of D2R agonists.

Citation

Klein Herenbrink, C., Verma, R., Lim, H. D., Kopinathan, A., Keen, A., Shonberg, J., …Lane, J. R. (2019). Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole. ACS Chemical Biology, 14(8), 1780-1792. https://doi.org/10.1021/acschembio.9b00342

• Journal Article Type: Article
• Acceptance Date: Jul 24, 2019
• Online Publication Date: Jul 24, 2019
• Publication Date: Aug 16, 2019
• Deposit Date: Jul 30, 2019
• Publicly Available Date: Jul 25, 2020
• Journal: ACS Chemical Biology
• Print ISSN: 1554-8929
• Electronic ISSN: 1554-8937
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 8
• Pages: 1780-1792
• DOI: https://doi.org/10.1021/acschembio.9b00342
• Keywords: Molecular Medicine; Biochemistry; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/2355472
• Publisher URL: https://pubs.acs.org/doi/10.1021/acschembio.9b00342