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. This emphasizes the necessity of employing novel chemical entities functioning through unique mechanisms to combat the growing threat of this infectious killer disease worldwide. In this perspective, we are applying the concept of Prof. Luis E. N. Quadri, who speculated that discovering new antibacterial drugs could be facilitated by focusing on a conditionally necessary pathway in the host-pathogen machinery. One such machinery is the mycobactin biosynthesis pathway (MBP), which helps in the mycobacterial life cycle and replication. Mycobactin (siderophore) is synthesized by the mycobactin megasynthase cluster, which includes 14 conditionally essential genes (mbtA-mbtN) and encodes a mixed nonribosomal peptide synthetase-polyketide synthase (NRPS-PKS) system. Of which the enzyme salicyl-AMP ligase (MbtA) plays a pivotal role. This makes it a promising endogenous target for identifying new lead molecules/inhibitors. Since the 2000s, nucleoside analogs have been the focus of much research as potential MbtA inhibitors. Since these have poor PK profiles, our research group is more diverted toward identifying non-nucleoside analogs. 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. Hence, we designed a small library (12 molecules) of mycobactin analogs keeping the necessary scaffold (diaryl-substituted pyrazoline (DAP)) intact and assessed their insilico stability using molecular docking simulations (AutoDock 4.2.6) and molecular dynamics simulations (GROMACS) to identify second-generation hit-compounds. 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. The six top-scoring compounds were evaluated for their ADMET (absorption-distribution-metabolism-excretion-toxicity) profile. The best molecule which revealed a good ADMET profile were taken up for MD simulation study (45ns). Results revealed that the designed compound GV02 (-8.53, 563.3nM), GV03 (-8.59, 508.51nM), GV04 (-8.26, 878.26nM), GV07, (-8.54, 553.44nM), GV08 (-8.80, 352.58nM), and GV09 (-8.61, 499.91nM) 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 intracellular activity.
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Design and in silico evaluation of some non-nucleoside MbtA inhibitors (pyrazoline-based mycobactin analogs) as antitubercular agents: On track to tackle tuberculosis
Published: 17 November 2022 by MDPI in The 26th International Electronic Conference on Synthetic Organic Chemistry session Computational Chemistry
Keywords: Antitubercular drug discovery; MbtA; Molecular docking; MD simulation; Mycobactin; Siderophores; Pyrazolines