MC-350013 and Corylin Emerge as Promising Neuroprotective Agents through Dual Targeting of xCT and GLT-1.

Studies have demonstrated the impact of alterations of glutamate homeostasis, involving particularly, its excitotoxicity effects in neurological diseases. As an essential neurotransmitter, glutamate is crucial in several physiological functions, and is regulated by two essential transporters, cystine-glutamate antiporter (xCT) and astrocytic glutamate transporter 1 (GLT-1). Dysfunction of these transporters is associated with a variety of neurological disorders as well as neurotoxic outcomes. This in-silico study evaluated selected novel GLT-1 modulators, and a chemical library for their neuroprotective potential through dual targeting of GLT-1 and xCT. Three novel GLT-1 enhancers and a total of 483 chemical compounds from Selleckchem were screened; of the latter, fifty-three compounds were selected based on favorable blood-brain barrier permeability, Lipinski's rule of five, and lipophilicity. We docked these 53 compounds and ultimately selected two candidates (MC-350013 and corylin) and MC-100093 as reference for molecular simulation studies based on their pharmacokinetic assessment, toxicity profile, and docking scores. MC-350013 showed the strongest binding affinities for both GLT-1 and xCT, with values of -9.5 and - 9.6 kcal/mol; corylin came second with - 9.0 and - 8.8 kcal/mol, respectively. Molecular simulations confirmed the stability of ligand-protein complexes, especially with MC-350013. Further, MM/PBSA analyses support the potential of MC-350013, with values of -17.95 kcal/mol for GLT-1 and - 28.11 kcal/mol for xCT; the corresponding values for corylin were - 26.59 and - 20.81 kcal/mol, respectively. These findings suggest that MC-350013 and corylin could be potential neuroprotective agents for modulating glutamate neurotoxicity, highlighting the value of in-silico drug discovery in identifying molecules targeting glutamate transporters.