Abstract
Detection of biased agonists for the serotonin 5-HT2A receptor can guide the discovery of safer and more efficient antipsychotic drugs. However, the rational design of such drugs has been hampered by the difficulty detecting the impact of small structural changes on signaling bias. To overcome these difficulties, we characterized the dynamics of ligand-receptor interactions of known biased and balanced agonists using molecular dynamics simulations. Our analysis revealed that interactions with residues S5.46 and N6.55 discriminate compounds with different functional selectivity. Based on our computational predictions, we selected three derivatives of the natural balanced ligand serotonin and experimentally validated their ability to act as biased agonists. Remarkably, our approach yielded compounds promoting an unprecedented level of signaling bias at the 5-HT2A receptor, which could help interrogate the importance of particular pathways in conditions like schizophrenia.
Footnotes
- Received December 2, 2014.
- Accepted February 6, 2015.
This work was funded by the Ministerio de Educación y Ciencia [Grants SAF2009-13609-C04-04 and SAF2009-13609-C04-01] and La MARATÓ de TV3 Foundation [Grant 091010]. M.M.-S. is supported by a doctoral fellowship from the University and Research Secretariat of the Catalan Government and the European Social Fund [2014FI_B2 00143]. J.S. acknowledges support from the Instituto de Salud Carlos III El Fondo Europeo de Desarrollo Regional (FEDER) [CP12/03139] and the GPCR-Ligand Interactions, Structures, and Transmembrane Signalling (GLISTEN) European Research Network. A.I. is supported by a Formación de Personal Investigador (FPI) grant from the Spanish Ministry of Economy and Competitiveness.
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- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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