Discovery of potent DNMT1 inhibitors against sickle cell disease using structural-based virtual screening, MM-GBSA and molecular dynamics simulation-based approaches

Abstract

Sickle cell disease (SCD) is an autosomal recessive genetic disorder affecting millions of people worldwide. A reversible and selective DNMT1 inhibitor, GSK3482364, has been known to decrease the overall methylation activity of DNMT1, resulting in the increase of HbF levels and percentage of HbF-expressing erythrocytes in an in vitro and in vivo model. In this study, a structure-based virtual screening was done with GSK3685032, a co-crystalized ligand of DNMT1 (PDB ID: 6X9K) with an IC50 value of 0.036 μM and identified 3988 compounds from three databases (ChEMBL, PubChem and Drug Bank). Using this screening method, we identified around 15 compounds with XP docking scores greater than −8 kcal/mol. Further, prime MM-GBSA calculations have been performed and found compound SCHEMBL19716714 with the highest binding free energy of −83.31 kcal/mol. Finally, four compounds were identified based on glide energy and ΔG bind scores that have the most binding with DG7, DG19, DG20 bases and Lys1535, His1507, Trp1510, Ser1230, which were required for the target enzyme inhibition. Furthermore, molecular dynamics simulation studies of top ligands validate the stability of the docked complexes by examining root mean square deviations, root mean square fluctuations, solvent accessible surface area, and radius of gyration graphs from simulation trajectories. These findings suggest that the top four hit compounds may be capable of inhibiting DNMT1 and that additional in vitro and in vivo studies will be essential to prove the clinical effectiveness of the selected lead compounds.