By means of a combined computational protocol involving hybrid ligand/receptor-based virtual
screening, molecular dynamics simulations and per-residue energy contribution, two compounds were suggested
as possible potential TB inhibitors. Using docking calculations, which were validated by molecular
dynamics simulations, binding free energy calculations indicated that the suggested compounds showed better
binding affinity with DprE1 when compared to CT319, a known DprE1 inhibitor. Results showed that
compounds retrieved from both pharmacophore and shape-similarity libraries pose crucial hydrogen bond
interactions with compound A and compound B. While compound B formed a hydrogen bond interaction
with Lys418, compound A formed a stable hydrogen bond interaction with Leu317. Furthermore, both compounds exhibited
apparent stability during molecular dynamics simulations with neither system exceeding an RMSD of 2.5 A.
MM/GBSA based binding free energy profile of both top ranked compounds further validated the docking result as both
of these hits showed a better binding free energy profile when compared with CT319. Also, the hydrogen bond interactions
between crucial residues and the top two ligands were well stabilized during the simulation time. However, while
further experimental investigations are required, the results obtained from this study could serve as a roadmap to assist
medicinal and biological chemists in the process of design and development of potential anti-TB drugs.