Identification of Potential Dual Negative Allosteric Modulators of Group I mGluR Family: A Shape Based Screening, ADME Prediction, Induced Fit Docking and Molecular Dynamics Approach Against Neurodegenerative Diseases

Background: Glutamate is the principal neurotransmitter in the human brain that exerts its effects through ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The mGluRs are a class of C GPCRs that play a vital role in various neurobiological functions, mGluR1 and mGluR5 are the two receptors distributed throughout the brain involved in cognition, learning, memory, and other important neurological processes. Dysfunction of these receptors can cause neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, X-fragile syndrome, anxiety, depression, etc., hence these receptors are high profile targets for pharmaceutical industries. Objective: The objective of our study is to find the novel dual negative allosteric modulators to regulate both mGluR1 and mGluR5. Methods: In this study, shape screening protocol was used to find the dual negative allosteric modulators for both mGluR1 and mGluR5 followed by ADME prediction, induced-fit docking (IFD) and molecular dynamics simulations. Further, DFT analysis and MESP studies were carried out for the selected compounds. Results: Around 247 compounds were obtained from the eMolecules database and clustered through the CANVAS module and filtered with ADME properties. Furthermore, IFD revealed that the top four compounds (16059796, 25004252, 4667236 and 11670690) having good protein-ligand interactions and binding free energies. The molecular electrostatic potential of the top compounds shows interactions in the amine group and the oxygen atom in the negative potential regions. Finally, molecular dynamics simulations were performed with all the selected as well as the reported compound 29 indicates that the screened hits have better stability of protein ligand complex. Conclusion: Hence, from the results, it is evident that top hits 16059796, 25004252, 4667236 and 11670690 could be a novel and potent dual negative allosteric modulators for mGluR1 and mGluR5.