Virtual screening, molecular docking, molecular dynamics simulations and free energy calculations to discover potential DDX3 inhibitors

Abstract

DEAD-box RNA helicase 3 (DDX3) is a versatile target that is elevated in several cancer cases besides being a validated target for viral infections. RK-33 is a well-known compound that has been used to target DDX3. In the current investigation, we have used several computational methods to discover RK-33 like compounds with greater affinity towards DDX3. Correspondingly, 95 compounds were obtained from PubChem and were subjected to molecular docking studies with DDX3 target (PDB code: 2I4I). The resultant two compounds were subjected to molecular dynamics simulation (MDS) studies to investigate the stabilities of the complex, performed for 100 ns in triplicates (100 ns x 3 ​= ​300 ns). The MDS results have shown that the identified compounds have established stable results during the evolution of the simulation across the triplicates, read according to root mean square deviation (RMSD), radius of gyration (Rg) and root mean square fluctuations (RMSF). Taken together we propose two compounds as alternatives to RK-33 with better binding affinity, stable MDS results and acceptable ADMET properties.