Staurosporine and four staurosporine derivatives were docked on the rhodopsin-based homology model of the M1 muscarinic acetylcholine receptor in order to localize the possible allosteric sites of this receptor. It was found that there were three major allosteric sites, two of which are located at the extracellular face of the receptor, and one in the intracellular domain of the receptor. In the present study, the localization of these binding sites is described for the first time. The present study confirms the existence of multiple allosteric sites on the M1 muscarinic receptor, and lays the ground for further experimental and computational analysis to better understand how muscarinic receptors are modulated via their allosteric sites. These findings will also help to design and develop novel drugs acting as allosteric modulators of the M1 receptor, which can be used in the treatment of the Alzheimer's disease.
Bibliographical noteFunding Information:
The authors thank Edward C. Hulme for providing the coordinates of the homology model of the M 1 muscarinic receptor, the anonymous reviewers for their constructive criticisms and Asya Varbanova for her thorough review of the manuscript and suggested improvements. This work was supported, in part, by grants from CONACYT and CGPI-IPN to J.G.T.F. L.M.E.F.’s research is supported by grants from the Department of Biochemistry, Structural Biology and Biophysics, and the Minnesota Supercomputing Institute, University of Minnesota.
- Allosteric sites
- Alzheimer's disease
- Docking simulations
- G-protein coupling receptors
- M muscarinic acetylcholine receptor
- Molecular dynamics