Computational Evaluation of 1, 1′-[(E)-Ethene-1, 2-Diyl] Dibenzene Derivatives As Modulators of GABAA Receptors

GABAA receptors are widely distributed throughout the central nervous system which plays an important role in inhibitory neurotransmission mediated by the pre-synaptic release of GABA (γ-amino butyric acid), a dominant inhibitory neurotransmitter at the GABAergic synapse. In neurodevelopmental disorders, the defective inhibitory GABAergic neurotransmission has been linked to cognitive dysfunction. Hence, modulation of these receptors may aid in improving cognition in these populations. Aim: Aim of this study was to investigate the binding affinity of 1, 1′-[(E)-Ethene-1, 2- diyl] dibenzene derivatives against benzodiazepine binding site of GABAA receptors. In our study, a total of fourty 1, 1′-[(E)-Ethene-1, 2-diyl] dibenzene derivatives were investigated. Ligand binding affinity and receptor conformational changes were determined by computational methods such as molecular docking and dynamic simulation studies using software such as Glide and Desmond (Schrodinger, LLC). Results: The apo, agonist and antagonist bound co-crystallized structure of GABAA receptors (PDB code: 6D6T, 4COF, 6CDU, and 6D1S) were docked with 43 conformers of fourty 1, 1′-[(E)-Ethene-1, 2- diyl] dibenzene derivatives generated using ligprep. Out of 40, compound-15 was found to exhibit a top-most docking score,-7.61 kcal/mol. The docking score of co-crystallized reference ligand (PDB code: 6D6T) was found to be -8.51 kcal/mol. Furthermore, molecular dynamic simulation studies were carried out at a time duration of 50 nsec, the conformational changes and the stability of receptor-ligand complex were determined based on the values of root mean square deviation (RMSD, A) and root mean square fluctuation (RMSF, nm). Conclusion: Overall, molecular docking and dynamic simulations showed that 1, 1′-[(E)-Ethene-1, 2-diyl] dibenzene derivative (compound-15) to posses better binding affinity in comparison to the reference ligand. Our future studies are aimed to carry out in-vitro and in-vivo pharmacological evaluation to explain the role of 1,1′-[(E)-Ethene-1,2-diyl]dibenzene derivatives in modulating GABAA receptors to reverse cognitive dysfunction in neurodevelopmental disorders.