Discovery of novel small molecule inhibitors targeting progranulin-sortilin: A virtual high throughput screening approach

Abstract 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 >47K 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. Drug likeliness and ADMET studies were also carried out. Results: The virtual screening workflow yielded 139 ligands. Two test ligands and a control were selected and further evaluated through molecular dynamics studies. Both the test ligands (1625 & 127) had comparative docking score (-5.96 & -6.46 kcal/mol) as that of control ligand (-6.21 kcal/mol respectively) and but better binding free energy (-54.66, -53.12 & -43.21 kcal/mol respectively). MD simulations confirmed the docking results for all the three ligands where our test ligand 1625 reached equilibrium quickly as compared to the rest. Our test compounds also showed favourable characteristics of a CNS acting drug and favourable ADMET properties. Conclusion: Our study results showed a promising CNS specific ligand as an inhibitor of PRGN-SORT interactions and has a potential to be developed as a drug through in-vitro and in-vivo studies.