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Review
. 2021 Jan;26(1):189-199.
doi: 10.1016/j.drudis.2020.10.006. Epub 2020 Oct 16.

Design of bivalent ligands targeting putative GPCR dimers

Boshi Huang  1 , Celsey M St Onge  1 , Hongguang Ma  1 , Yan Zhang  2
Affiliations
Review

Design of bivalent ligands targeting putative GPCR dimers

Boshi Huang et al. Drug Discov Today. 2021 Jan.

Abstract

G protein-coupled receptors (GPCRs) have been exploited as primary targets for drug discovery, and GPCR dimerization offers opportunities for drug design and disease treatment. An important strategy for targeting putative GPCR dimers is the use of bivalent ligands, which are single molecules that contain two pharmacophores connected through a spacer. Here, we discuss the selection of pharmacophores, the optimal length and chemical composition of the spacer, and the choice of spacer attachment points to the pharmacophores. Furthermore, we review the most recent advances (from 2018 to the present) in the design, discovery and development of bivalent ligands. We aim to reveal the state-of-the-art design strategy for bivalent ligands and provide insights into future opportunities in this promising field of drug discovery.

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Conflict of interest statement

Conflicts of interest

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
(a) A general schematic diagram for homobivalent and heterobivalent ligands. (b) The chemical structures of the bivalent ligand KDN21 and its two monomeric counterparts, NTI and GNTI. (c) The chemical structures of the bivalent ligand MCC22 and the two lead compounds oxymorphone and TAK-220.
Figure 2.
Figure 2.
(a) The chemical structure of cyclofenilacrylic acid-based bivalent ligand AK-15b. (b) The chemical structures of SR141617A, PPHT, the initially designed CBR1-D2R bivalent ligands and SAR explorations derived from SR141617A. (c) The chemical structure of the MOR-CCR5 bivalent ligand VZMC001. (d) The chemical structures of eticlopride, NT(8–13) and designed D2R–NTS1R bivalent ligands, (e) The chemical structures of MTEP, DAPT, DAP, linkers and mGluR5–D2R bivalent ligand MQ-22a.
Figure 3.
Figure 3.
(a) The chemical structures of the lead compound M100907 and the bivalent compound SG-15. (b) The chemical structure of the bivalent compound CS-6c. (c) The chemical structures of the hMC4R antagonist, hMC4R agonist and bivalent compounds CJL-1-124 and CJL-5-74. (d) The chemical structures of the lead compound NAPS and the bivalent compounds DP-12 and DP-13.
Figure 4.
Figure 4.
(a) The chemical structures of the lead compounds oxycodone, tetrapeptide and JWH-018, and the bivalent compounds SD-11 and SD-19. (b) The chemical structure of the MOR–CXCR4 bivalent ligand VZMX001 (with attachment points shown). (c) The chemical structures of the DOR antagonist (Tyr-Tic-OH), MOR antagonist (H-Tyr-Pro-Phe-D1Nal-NH2), and the bivalent compound D24M. (d) The chemical structures of the MOR agonist hydromorphone, the D2-likeR agonist DPAT and antagonist DAP, and the bivalent compound MQ-12d.
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