Discovery of Small‐Molecule Inhibitors Targeting Progranulin‐Sortilin: An in‐silico Approach Using Molecular Docking, Molecular Dynamics Simulations, and DFT Studies

Abstract

AbstractIntroduction: 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 screened ligands. 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. According to DFT studies, the test ligands 127 and 1625 had FMO (HOMO‐LUMO) energy gaps of 8.86 eV and 9.83 eV, respectively, that were lesser than the control ligand (9.89 eV). Additionally, FMO energy gap of the test ligands and the control ligand were in agreement with the results of docking. MEP diagram provided the picture of electron rich, neutral and electron deficient surface of the test ligands and that of the control with respective color code red, green and blue. 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.