Taxifolin as dual inhibitor of Mtb DNA gyrase and isoleucyl-tRNA synthetase: in silico molecular docking, dynamics simulation and in vitro assays
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DNA gyrase and aminoacyl-tRNA synthetases are two essential bacterial enzymes involved in DNA replication, transcription and translation. Flavonoids are plant secondary metabolites with variable phenolic structures. In this study, eight flavonoids structurally similar to quercetin were selected and their ADMET properties were evaluated. Molecular docking and free energy calculations were carried out to examine the binding of these flavonoids to the ATP-binding site and editing domain of DNA gyrase and Isoleucyl-tRNA synthetase, respectively. Taxifolin was found out to be the top lead molecule in both the docking studies with a good number of interactions with the active site amino acids. Further, binding of taxifolin to the proteins was extensively studied using 50 ns molecular dynamics simulation. In vitro anti-tuberculosis activity of taxifolin was evaluated and compared with the standard drugs. Minimal inhibition concentration of taxifolin was found to be ≤ 12.5 μg/ml.
KeywordsTuberculosis DNA gyrase Isoleucyl-tRNA synthetase Flavonoids Taxifolin Dual inhibitor
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Conflict of interest
The authors declare that there is no conflict of interest.
- Brown AK, Papaemmanouil A, Bhowruth V, Bhatt A, Dover LG, Besra GS (2007) Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II. Microbiology 153:3314–3322. https://doi.org/10.1099/mic.0.2007/009936-0 CrossRefPubMedGoogle Scholar
- Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749. https://doi.org/10.1021/jm0306430 CrossRefPubMedGoogle Scholar
- Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49:6177–6196. https://doi.org/10.1021/jm051256o CrossRefPubMedPubMedCentralGoogle Scholar
- Tripathi RP, Verma SS, Pandey J, Agarwal KC, Chaturvedi V, Manju YK, Srivastva AK, Gaikwad A, Sinha S (2006) Search of antitubercular activities in tetrahydroacridines: synthesis and biological evaluation. Bioorg Med Chem Lett 16:5144–5147. https://doi.org/10.1016/j.bmcl.2006.07.025 CrossRefPubMedGoogle Scholar
- Zheng Y, Jiang X, Gao F, Song J, Sun J, Wang L, Sun X, Lu Z, Zhang H (2014) Identification of plant-derived natural products as potential inhibitors of the Mycobacterium tuberculosis proteasome. BMC Complement Altern Med 14:400. https://doi.org/10.1186/1472-6882-14-400 CrossRefPubMedPubMedCentralGoogle Scholar
- Zumla AI, Gillespie SH, Hoelscher M, Philips PP, Cole ST, Abubakar I, McHugh TD, Schito M, Maeurer M, Nunn AJ (2014) New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects. Lancet Infect Dis 14:327–340. https://doi.org/10.1016/s1473-3099(13)70328-1 CrossRefPubMedGoogle Scholar