In Silico Design and Investigation of Novel Thiazetidine Derivatives as Potent Inhibitors of PrpR in Mycobacterium tuberculosis.

Tuberculosis is one of the most life-threatening acute infectious diseases diagnosed in humans. In the present investigation, a series of 16 new disubstituted 1,3-thiazetidines derivatives is designed, and investigated via various in silico methods for their potential as anti-tubercular agent by evaluating their ability to block the active site of PrpR transcription factor protein of Mycobacterium tuberculosis. The efficacy of the molecules was initially assessed with the help of AutoDock Vina algorithm. Further Glide module is used to redock the previously docked complexes. The binding energies and other physiochemical properties of the designed molecules were evaluated using the Prime-MM/GBSA and the QikProp module, respectively. The results of docking revealed the nature, site of interaction and the binding affinity between the proposed candidates and the active site of PrpR. Further the inhibitory effect of the scaffolds was predicted and evaluated employing a machine learning-based algorithm and was used accordingly. Further, the molecular dynamics simulation studies ascertained the binding characteristics of the unique 13, when analysed across a time frame of 100 ns with GROMACS software. The results show that the proposed 1,3-thiazetidine derivatives such as 10, 11, 13 and 14 could be potent and selective anti-tubercular agents as compared to the standard drug Pyrazinamide. Finally, this study concludes that designed thiazetidines can be employed as anti-tubercular agents. Undeniably, the results may guide the experimental biologists to develop safe and non-toxic drugs against tuberculosis by demanding further in vivo and in vitro analyses.