GABAA Receptor-Benzodiazepine Binding Site Interaction Analysis of 9Hxanthen- 9-One Derivatives – A Molecular Docking and Dynamic Simulation Study

Abstract

Background: Synaptic plasticity is the change occurring at the synaptic junction (synapse) which can strengthen or weaken over time, in response to increases or decreases in their activity. A co-ordinated and balanced function of glutamatergic (excitatory) and γ-amino butyric acid (GABA)-ergic (inhibitory) neurotransmission are essential for long-term potentiation to store information, create and remember new memories. However, in neurodegenerative diseases, hyperactive glutamatergic, defective GABAergic neurons and loss of synaptic plasticity leads to impaired cognition. Targeting the benzodiazepine site of postsynaptic GABAergic neurons may facilitate the binding of GABA and thereby increase the amplitude of GABAergic inhibitory neurotransmission.

Aim: The aim of this study was to determine the binding affinity and molecular dynamic characterization of selective 9H-Xanthen-9-one derivatives with benzodiazepine site of GABAA receptors.

Methods: Molecular docking and dynamic simulation study was performed using Glide and Desmond (Schrödinger, LLC) respectively.

Results: The apo, agonist and antagonist bound co-crystallized structure of GABAA receptor (PDB code: 6D6T, 4COF, 6CDU, and 6D1S) were docked with a total of 63 conformers of eleven 9H -Xanthen-9-one derivatives generated using ligprep. Out of 11, compound-5 was found to exhibit a lowest docking score of - 8.843 kcal/mol in comparison to reference ligand (-7.036 kcal/mol). Postdocking, molecular dynamic simulation studies were carried out at a time duration of 50 nsec, the conformational changes of the receptor and the stability of receptor-ligand complex were determined using the values of root mean square deviation (RMSD, Å) and root mean square fluctuation (RMSF, nm).

Conclusion: To conclude, molecular docking and dynamic simulations has predicted that 9H -xanthen-9-one derivative was found to exhibit greater binding affinity than reference ligand. In future, in-vitro and in-vivo studies will be carried out in order to determine the role of 9H-xanthen-9-one derivatives in rescuing defective GABAergic neurotransmission in neurodegenerative diseases.

Keywords: GABAA receptor, 9HXanthen-9-one derivatives, a molecular docking,dynamic simulation study