In silico evaluation of curcumin as a neuroprotective ligand targeting mGluR5

Metabotropic glutamate receptor 5 (mGluR5) supports synaptic plasticity and neurogenesis, making it a therapeutic target in conditions with neuronal loss. However, most known mGluR5 ligands are synthetic molecules with limited safety or brain penetrance, and the interaction of natural neuroprotective compounds with mGluR5 remains inadequately explored. Curcumin, a polyphenolic compound from Curcuma longa with documented neuroprotective and neurogenic effects, has not previously been evaluated as a potential mGluR5-binding ligand. This study tested whether curcumin engages mGluR5 with stability comparable to the reference ligand 2-Chloro-5-hydroxyphenylglycine (CHPG). Molecular docking defined the pose, and molecular dynamics for one microsecond evaluated receptor–ligand stability, flexibility, compactness, solvent exposure, hydrogen bonding, essential dynamics, and binding energetics by molecular mechanics/Poisson-Boltzmann surface area. Both complexes equilibrated and remained stable, with similar root mean square deviation plateaus near 0.49 nm and a steady radius of gyration near 1.6 nm, indicating preserved global structure. Curcumin produced a modest increase in local flexibility and a small rise in solvent accessible surface area, consistent with slightly broader but still well contained motions. Hydrogen bonds were present for both ligands but were less persistent for curcumin; nevertheless, the total binding free energy remained favorable for curcumin and more favorable for CHPG. Principal component analysis showed both systems sampling the same conformational basin, supporting comparable overall dynamics. Taken together, the data show that curcumin engages the receptor through hydrophobic packing with limited polar anchoring, and maintains receptor integrity. These features support curcumin as an mGluR5 ligand, suggesting potential relevance to neuroprotective modulation.