Abstract
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.
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References
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
Brvar M, Perdih A, Renko M, Anderluh G, Turk D, Solmajer T (2012) Structure-based discovery of substituted 4,5′-bithiazoles as novel DNA gyrase inhibitors. J Med Chem 55:6413–6426. https://doi.org/10.1021/jm300395d
Cho S, Lee HS, Franzblau S (2015) Microplate alamar blue assay (MABA) and low oxygen recovery assay (LORA) for Mycobacterium tuberculosis. Methods Mol Biol 1285:281–292. https://doi.org/10.1007/978-1-4939-2450-9_17
Collin F, Karkare S, Maxwell A (2011) Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Appl Microbiol Biotechnol 92:479–497. https://doi.org/10.1007/s00253-011-3557-z
Cushnie TT, Lamb AJ (2005) Antimicrobial activity of flavonoids. Int J Antimicrob Agents 26:343–356
Dawson R, Diacon A (2013) PA-824, moxifloxacin and pyrazinamide combination therapy for tuberculosis. Expert Opin Investig Drugs 22:927–932. https://doi.org/10.1517/13543784.2013.801958
Dodson GG, Lane DP, Verma CS (2008) Molecular simulations of protein dynamics: new windows on mechanisms in biology. EMBO Rep 9:144–150. https://doi.org/10.1038/sj.embor.7401160
Fayaz SM, Rajanikant GK (2014) Ensemble pharmacophore meets ensemble docking: a novel screening strategy for the identification of RIPK1 inhibitors. J Comput Aided Mol Des 28:779–794. https://doi.org/10.1007/s10822-014-9771-x
Floyd K, Glaziou P, Zumla A, Raviglione M (2018) The global tuberculosis epidemic and progress in care, prevention, and research: an overview in year 3 of the End TB era. Lancet Respir Med 6:299–314. https://doi.org/10.1016/s2213-2600(18)30057-2
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
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
Fukunaga R, Yokoyama S (2006) Structural basis for substrate recognition by the editing domain of isoleucyl-tRNA synthetase. J Mol Biol 359:901–912. https://doi.org/10.1016/j.jmb.2006.04.025
Hendrich AB (2006) Flavonoid-membrane interactions: possible consequences for biological effects of some polyphenolic compounds. Acta Pharmacol Sin 27:27–40. https://doi.org/10.1111/j.1745-7254.2006.00238.x
Hodgson J (2001) ADMET–turning chemicals into drugs. Nat Biotechnol 19:722–726. https://doi.org/10.1038/90761
Karkare S, Chung TT, Collin F, Mitchenall LA, McKay AR, Greive SJ, Meyer JJ, Lall N, Maxwell A (2013) The naphthoquinone diospyrin is an inhibitor of DNA gyrase with a novel mechanism of action. J Biol Chem 288:5149–5156. https://doi.org/10.1074/jbc.M112.419069
Koul A, Arnoult E, Lounis N, Guillemont J, Andries K (2011) The challenge of new drug discovery for tuberculosis. Nature 469:483–490. https://doi.org/10.1038/nature09657
Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview. Sci World J 2013:16. https://doi.org/10.1155/2013/162750
Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51:2778–2786. https://doi.org/10.1021/ci200227u
Lyne PD, Lamb ML, Saeh JC (2006) Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J Med Chem 49:4805–4808. https://doi.org/10.1021/jm060522a
Maharaj Y, Soliman ME (2013) Identification of novel gyrase B inhibitors as potential anti-TB drugs: homology modelling, hybrid virtual screening and molecular dynamics simulations. Chem Biol Drug Des 82:205–215. https://doi.org/10.1111/cbdd.12152
Mdluli K, Ma Z (2007) Mycobacterium tuberculosis DNA gyrase as a target for drug discovery. Infect Disord Drug Targets 7:159–168. https://doi.org/10.2174/187152607781001763
Plaper A, Golob M, Hafner I, Oblak M, Solmajer T, Jerala R (2003) Characterization of quercetin binding site on DNA gyrase. Biochem Biophys Res Commun 306:530–536
Pravda L, Berka K, Svobodova Varekova R, Sehnal D, Banas P, Laskowski RA, Koca J, Otyepka M (2014) Anatomy of enzyme channels. BMC Bioinform 15:379. https://doi.org/10.1186/s12859-014-0379-x
Raviglione M, Sulis G (2016) Tuberculosis 2015: burden, challenges and strategy for control and elimination. Infect Dis Rep 8:6570. https://doi.org/10.4081/idr.2016.6570
Rohini K, Shanthi V (2017) Discovery of potent neuraminidase inhibitors using a combination of pharmacophore-based virtual screening and molecular simulation approach. Appl Biochem Biotechnol. https://doi.org/10.1007/s12010-017-2625-y
Sassanfar M, Kranz JE, Gallant P, Schimmel P, Shiba K (1996) A eubacterial Mycobacterium tuberculosis tRNA synthetase is eukaryote-like and resistant to a eubacterial-specific antisynthetase drug. Biochemistry 35:9995–10003. https://doi.org/10.1021/bi9603027
Takekoshi S, Nagata H, Kitatani K (2014) Flavonoids enhance melanogenesis in human melanoma cells. Tokai J Exp Clin Med 39:116–121
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
Veau D, Krykun S, Mori G, Orena BS, Pasca MR, Frongia C, Lobjois V, Chassaing S, Lherbet C, Baltas M (2016) Triazolophthalazines: easily accessible compounds with potent antitubercular activity. ChemMedChem 11:1078–1089. https://doi.org/10.1002/cmdc.201600085
Vondenhoff GH, Van Aerschot A (2011) Aminoacyl-tRNA synthetase inhibitors as potential antibiotics. Eur J Med Chem 46:5227–5236. https://doi.org/10.1016/j.ejmech.2011.08.049
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
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
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Kozhikkadan Davis, C., Nasla, K., Anjana, A.K. et al. Taxifolin as dual inhibitor of Mtb DNA gyrase and isoleucyl-tRNA synthetase: in silico molecular docking, dynamics simulation and in vitro assays. In Silico Pharmacol. 6, 8 (2018). https://doi.org/10.1007/s40203-018-0045-5
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DOI: https://doi.org/10.1007/s40203-018-0045-5