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Introduction: Reduction in progranulin (PGRN) have been associated with various neurodegenerative diseases. PGRN binds with high affinity to sortilin (SORT), a membrane transporter, resulting in its cellular uptake and eventual degradation in the lysosome. Inhibition of the SORT‐PGRN interaction has the potential to increase PGRN levels up to 2.5‐fold. Methodology: A virtual screening of curated CNS library of >47 K ligands was done with sortilin receptor (6X3L) through virtual screening workflow in Schrodinger suite. Co‐crystallised ligand was used as a positive control. Docking was done through HTVS, then SP and finally XP model followed by binding free energy calculations (MMGBSA). Based on the result analysis of molecular docking, binding free energy and interactions, docked complexes were chosen for molecular dynamics (MD) studies. DFT studies and MEP plotting were carried out for the …