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

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.Communicated by Ramaswamy H. Sarma.

 

Comments:

That's an impressive study! It sounds like a comprehensive approach was taken to identify potential compounds for inhibiting DNMT1, with a particular focus on increasing HbF levels to alleviate the effects of sickle cell disease. Identifying compounds through virtual screening and then validating their potential through molecular dynamics simulations is a robust methodology.

The involvement of specific residues like Lys1535, His1507, Trp1510, and Ser1230 in the binding of the identified compounds suggests a targeted interaction with the DNMT1 enzyme, which could be crucial for inhibition.

The next steps, as you've mentioned, involve in vitro and in vivo studies to further assess the clinical effectiveness and safety profile of these identified lead compounds. It's an exciting prospect for potential therapeutic interventions in sickle cell disease.

Ramaswamy H. Sarma's contribution seems significant in this research. Have you been involved in this study, or are you looking to delve deeper into this topic?

Related Products

Cat.No.	Product Name	Information
E1046	GSK3685032	GSK3685032 is a non-time-dependent, highly selective enzymatic inhibitor of DNA methyltransferase (DNMT1) with IC50 of 0.036 μM, and over 2500-fold more selective than DNMT3A/3L and DNMT3B/3L.

Related Targets

DNA Methyltransferase