Exploring novel ligands for mGluR5: Design, computational analysis, and protein-ligand interaction studies

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors activated by glutamate. A series of 90 novel compounds have been assessed as mGluR5 receptor antagonists. These compounds, selected post-ADMET filtering according to Lipinski's rule of five, represent structurally innovative ligands inspired by promising existing ones. Utilizing the FlexX program, the ligands were docked alongside the reference compound SIB1757 to mGluR5. Docking simulations unveiled compound 14, featuring an ortho-substituted moiety, as the most promising with a binding affinity of -47 kcal/mol, followed by compound 8 at -41 kcal/mol. A total of 31 docked molecules exhibited superior binding affinity compared to reference compounds. Subsequent molecular dynamics simulations over 100 ns confirmed the stability of protein-ligand complexes, establishing the efficacy of the selected compounds as negative allosteric modulators of mGluR5.G