Computer-aided Identification of Novel DprE1 Inhibitors as Potential Anti-TB Lead Compounds: A Hybrid Virtual-screening and Molecular Dynamics Approach

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.