Discovery of potent DNMT1 inhibitors against sickle cell disease using structural-based virtual screening, MM-GBSA and molecular dynamics simulation-based approaches
Chandu Ala 1, Renuka Parshuram Joshi 1, Pragya Gupta 2 3, Sivaprakash Ramalingam 2 3, Murugesan Sankaranarayanan 1

Sickle cell disease (SCD) is definitely an autosomal recessive genetic disorder affecting huge numbers of people worldwide. A reversible and selective DNMT1 inhibitor, GSK3482364, is known to lower the general methylation activity of DNMT1, inducing the increase of HbF levels and number of HbF-expressing erythrocytes within an in vitro as well as in vivo model. Within this study, a structure-based virtual screening ended with GSK3685032, a co-crystalized ligand of DNMT1 (PDB ID: 6X9K) by having an IC50 worth of .036 |¨¬M and identified 3988 compounds from three databases (ChEMBL, PubChem and Drug Bank). By using this screening method, we identified around 15 compounds with XP docking scores more than -8 kcal/mol. Further, prime MM-GBSA calculations happen to be performed and located compound SCHEMBL19716714 using the greatest binding free energy of -83.31 kcal/mol. Finally, four compounds were identified according to glide energy and |¡èG bind scores which have probably the most binding with DG7, DG19, DG20 bases and Lys1535, His1507, Trp1510, Ser1230, that have been needed for that target enzyme inhibition. In addition, molecular dynamics simulation studies of top ligands validate the soundness from the docked complexes by analyzing root mean square deviations, root mean square fluctuations, solvent accessible area, and radius of gyration graphs from simulation trajectories. These bits of information claim that the very best four hit compounds may manage to inhibiting DNMT1 which additional in vitro as well as in vivo studies is going to be necessary to prove the clinical effectiveness from the selected lead compounds.