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Structure-based Design and Discovery of New M2 Receptor Agonists

Written By Monday 20 December 2021 Add Comment Edit

. 2017 Nov 22;60(22):9239-9250.

doi: 10.1021/acs.jmedchem.7b01113. Epub 2017 Nov 13.

Structure-Based Design and Discovery of New M 2 Receptor Agonists

Anne Stößel 3 , Katrin Eitel 3 , Celine Valant 4 , Sabine Albold 4 , Harald Huebner 3 , Dorothee Möller 3 , Mary J Clark 5 , Roger K Sunahara 5 , Arthur Christopoulos 4 , Brian K Shoichet 1 , Peter Gmeiner 3

Affiliations

  • PMID: 29094937
  • PMCID: PMC5836741
  • DOI: 10.1021/acs.jmedchem.7b01113

Free PMC article

Structure-Based Design and Discovery of New M 2 Receptor Agonists

Inbar Fish  et al. J Med Chem. .

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Abstract

Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.

Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1

(A) The crystal structure of M2 active state in a complex with iperoxo (PDB 4MQS). Residues Asn6.52 and Asp3.32 are represented as sticks and hydrogen bonds as red broken lines. Iperoxo fits tightly in the binding site. (B–D) Docking poses of pilocarpine (B), muscarine (C), and arecoline (D) in the M2 active state structure.

Figure 2
Figure 2

Structure-based discovery of new muscarinic agonists: project flow. Structure-guided design from the M2R/iperoxo complex (top left) led to 19 candidate ligands chemically distinct from previous agonists. Optimization led to the improved compound 28, a new agonist scaffold (bottom right). A docking screen of a large fragment library (bottom middle) led to three still newer agonists (bottom left).

Figure 3
Figure 3

(A) Superposition of compound 17 (green) and compound 3 (purple). Residues Asn6.52, Asp3.32, and Ser107 are represented as sticks. Both compounds hydrogen bond (black broken lines) with Asn6.52. (B) Superposition between the iperoxo (silver) pose in the M2R active state structure (PDB 4MQS) and the docked pose of compound 3 (purple). Both compounds appear to hydrogen bond with Asn6.52, ion pair with Asp3.32, and are enclosed by an aromatic cage composed of Tyr104, Tyr403, and Tyr426.

Figure 4
Figure 4

Detailed investigation of the new muscarinic agonists 3 and 28. (A–C) Binding behavior at whole cells expressing the muscarinic receptor subtypes M1 (A), M2 (B), and M3 (C) in comparison to the natural ligand acetylcholine. (D–G) M2 selective signaling of 28 indicated by a weak activation of M1 and M3 stimulated IP accumulation (D and E, respectively) and full agonist effect in M2 mediated GTPγS binding (F) and inhibition of cAMP accumulation (G). (H) M2 mediated β-arrestin recruitment displays full agonist effect for 28. (I–K) Downstream signaling shows M2 selective agonist properties for 28 as determined in a ERK1/2 phosphorylation assay for M1 (I), M2 (J), and M3 (K).

Figure 5
Figure 5

Docking poses of compounds 29 (A), 30 (B), and 33 (C) in the M2R active state structure (PDB 4MQS). Residues Asn6.52, Asp3.32, Ser107, and Tyr403 are represented as sticks. Hydrogen bonds are represented in black.

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Structure-based Design and Discovery of New M2 Receptor Agonists

Source: https://pubmed.ncbi.nlm.nih.gov/29094937/

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