A DFT approach to discriminate the antagonist and partial agonist activity of ligands binding to the NMDA receptor

ABSTRACT

The activation of N-methyl-D-aspartate receptors is found to be intimately associated with neurodegenerative diseases which make them promising therapeutic targets. Despite the significantly increasing multidisciplinary interests centred on this ionotropic channel, design of new ligands with intended functional activity remains a great challenge. In this article, a computational study based on density functional theory is presented to understand the structural factors of ligands determining their function as antagonists and partial agonists. With this aim, the GluN1 subunit is chosen as being one of the essential components in the activation mechanism, and quantum chemical calculations are implemented for 30 antagonists and 30 partial agonists known to bind to this subunit with different binding affinities. Several quantum chemical descriptors are investigated which might unlock the difference between antagonists and partial agonists.

KEYWORDS:

• Chemical descriptor
• chemical hardness
• HOMO-LUMO energies
• NMDA receptor

Acknowledgments

Freija De Vleeschouwer acknowledges the Research Foundation-Flanders (FWO) for a postdoctoral fellowship (1227014 N). Frank De Proft acknowledges the FWO and the Free University of Brussels (VUB) for continuous support to their research group, in particular the VUB for awarding a Strategic Research Program to the ALGC research group started on 1 January 2013. Viktorya Aviyente is grateful to the Bogazici University Research Funds (BAP 8780) for financial support. The computations were performed using the computational facilities of the Polymer Research Center (DPT-2009K120520).

4. Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Bogazici University Research Funds [grant number BAP 8780]; Fonds Wetenschappelijk Onderzoek [grant number 1227014 N].