Structure-Guided Screening for Functionally Selective D-2 Dopamine Receptor Ligands from a Virtual Chemical Library

Männel B, Jaiteh M, Zeifinan A, Randakova A, Möller D, Hübner H, Gmeiner P, Carlsson J (2017)

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2017

Journal

Publisher: AMER CHEMICAL SOC

Book Volume: 12

Pages Range: 2652-2661

Journal Issue: 10

DOI: 10.1021/acschembio.7b00493

Abstract

Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D-2 dopamine receptor (D2R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D2R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D2R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13-000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D2R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and beta-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated beta-arrestin recruitment (EC50 = 320 nM, E-max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

Uppsala University Sweden (SE)

How to cite

APA:

Männel, B., Jaiteh, M., Zeifinan, A., Randakova, A., Möller, D., Hübner, H.,... Carlsson, J. (2017). Structure-Guided Screening for Functionally Selective D-2 Dopamine Receptor Ligands from a Virtual Chemical Library. ACS Chemical Biology, 12(10), 2652-2661. https://dx.doi.org/10.1021/acschembio.7b00493

MLA:

Männel, Barbara, et al. "Structure-Guided Screening for Functionally Selective D-2 Dopamine Receptor Ligands from a Virtual Chemical Library." ACS Chemical Biology 12.10 (2017): 2652-2661.

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