Speaker
Description
The WHO database shows that Mycobacterium tuberculosis has become an epidemic worldwide due to its pathogenicity and virulence, which have magnified its infectiousness. The situation becomes grimmer with the prevalence of MDR-TB, XDR-TB, emergence of cross-resistance, ineffectiveness of novel therapeutic targets, failure of novel medications in clinical trials, currently available drugs losing their therapeutic efficacy, lack of drug discovery efforts due to poor ROI, and the existence of co-infections, i.e., HIV, TB, COVID, and HIV-TB-COVID. Following our prior studies described by Stirret et al., 2008, Ferreras et al., 2011, & Shyam et al., 2021 herein we focus on exploring pyrazoline-based mycobactin analogs (non-specific mycobactin biosynthesis inhibitors) targeting MbtA enzyme (1st step of mycobactin biosynthesis) with a hope of finding a more potent analog showing a high affinity for MbtA. Design strategy involves retaining the structural features of mycobacterial siderophores. Herein, we designed a small library (12 molecules) of mycobactin analogs keeping the necessary scaffold (diaryl-substituted pyrazoline (DAP)) intact and assessed their stability using in silico tools. To find the binding modalities and inhibitory profile of the proposed compounds, they were docked in the active site of the MbtA receptor (by analogy with the homologous structure PDB: 1MDB). The lowest energy conformation of each docked ligand (best score) was visualized. All compounds were evaluated for their ADMET (absorption-distribution-metabolism-excretion-toxicity) profile. The best molecule which revealed a good ADMET profile was taken up for MD simulation study (45ns). Results revealed that the designed compounds GV08 (-8.80kcal/mol, 352.58nM), GV09 (-8.61kcal/mol, 499.91nM), GV03 (-8.59kcal/mol, 508.51nM), and GV07, (-8.54 kcal/mol, 553.44nM) had good docking score and inhibition constant. Of these GV08 showed a good ADME profile with all major parameters lying in the acceptable ranges. They also showed the least toxicity with no hepatotoxicity and skin sensitization. MD simulation studies of GV08 also suggest that the protein-ligand complex is stable throughout the simulation as was evidenced by RMSD, RMSF, and H-bond plots. The future scope invalidates these findings through synthesis, characterization, and biological activity.