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

Fish I, Stößel A, Eitel K, Valant C, Albold S, Hübner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P (2017)


Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2017

Journal

Publisher: AMER CHEMICAL SOC

Book Volume: 60

Pages Range: 9239-9250

Journal Issue: 22

DOI: 10.1021/acs.jmedchem.7b01113

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 M-2 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.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

How to cite

APA:

Fish, I., Stößel, A., Eitel, K., Valant, C., Albold, S., Hübner, H.,... Gmeiner, P. (2017). Structure-Based Design and Discovery of New M-2 Receptor Agonists. Journal of Medicinal Chemistry, 60(22), 9239-9250. https://dx.doi.org/10.1021/acs.jmedchem.7b01113

MLA:

Fish, Inbar, et al. "Structure-Based Design and Discovery of New M-2 Receptor Agonists." Journal of Medicinal Chemistry 60.22 (2017): 9239-9250.

BibTeX: Download