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Application of DFT Descriptors For The Discrimination of Agonist and Antagonist Activity of Ligands Binding to The NMDA Receptor

This paper is available in a repository.
This paper is available in a repository.

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Abstract

N-Methyl-D-Aspartate (NMDA), which is a member of ionotropic glutamate receptors (iGluR) becomes active via binding of glycine and glutamate to the subunits of the receptor. Thus, the binding sites of these subunits are important targets for pharmaceutical research. NMDA receptor has two distinctive behaviours which makes it more prominent for medical researches 1. The first one is the inactivation of NMDA during its recessing period, and the second one is the "exitotoxic cell death" due to the prolonged stimulation of the receptor. Regulation of receptor activity by introducing partial agonist-antagonist ligands to the glycine and glutamate sites became a promising strategy for the treatment of neuropsychiatric disorders, which are related with dysfunction of NMDA. In this study, quantum chemical calculations are implemented to the ligands for the major subfamily of glutamate receptors, N-methyl-D-aspartate (NMDA). In this manner molecular properties playing a role in ligand binding to NMDA are investigated. Various quantum chemical descriptors are calculated to understand the link between chemical traits of molecules and their activities. These descriptors are further used to discriminate the partial agonism-antagonism nature of the ligands. A number of ligands which bind to the glycine binding site NR1 subunit with different activities 2-5 are selected and calculations are carried out using B3LYP with the PCM solvent model in water by utilizing the Gaussian09 program package. The next step of this project will be to connect these molecular descriptors to their activities in order to design a robust QSAR model for the ligands of the NMDA receptor. This will open new opportunities for the drug design in virtual screening and synthesis of novel classes of ligands for glutamate receptors.