Abstract
Background: Galactofuranoyltransferase-2 (GlfT2) enzyme involved in the galactan polymerization of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an important component of the mycobacterial cell wall.
Objective: With the existing challenge, the study focused on identifying certain commercially available flavonoids through molecular docking studies against the Galactofuranoyltransferase-2 enzyme.
Methods: The initial pharmacokinetic screening was carried out using Lipinski’s rule of 5 with the help of Molinspiration software. In this perspective, Apigenin, Kaempferol, Rutin, Silibinin and Vitexicarpin were selected for the current study. Except for rutin all other selected flavonoids did not show any violations and were thereby selected for the docking studies using AutoDock 4.2.
Results: The docking results showed that the selected flavonoids have excellent binding energy values between −8.98 to −6.58 kcal/mol against the GlfT2 enzyme. The theoretical inhibition constant was found to be in the range of 260.90 nM to 15.13 μM which coincides with the binding energies of the selected compounds.
Conclusion: From the selected flavonoids, Silibinin showed excellent binding scores and has the potential to inhibit the GlfT2 enzyme. Silibinin could act as a novel GlfT2 inhibitor with promising therapeutic activity with low toxicity profile against tuberculosis.
Keywords: Galactofuranoyltransferase-2, binding energy, inhibition constant, flavonoids, silibinin, mycolic acid.
Graphical Abstract
[1]
Crick, D.C.; Mahapatra, S.; Brennan, P.J. Biosynthesis of the arabinogalactan-peptidoglycan complex of Mycobacterium tuberculosis. Glycobiology, 2001, 11(9), 107R-118R.
[http://dx.doi.org/10.1093/glycob/11.9.107R] [PMID: 11555614]
[http://dx.doi.org/10.1093/glycob/11.9.107R] [PMID: 11555614]
[2]
Stevenson, G.; Neal, B.; Liu, D.; Hobbs, M.; Packer, N.H.; Batley, M.; Redmond, J.W.; Lindquist, L.; Reeves, P. Structure of the O antigen of Escherichia coli K-12 and the sequence of its rfb gene cluster. J. Bacteriol., 1994, 176(13), 4144-4156.
[http://dx.doi.org/10.1128/jb.176.13.4144-4156.1994] [PMID: 7517391]
[http://dx.doi.org/10.1128/jb.176.13.4144-4156.1994] [PMID: 7517391]
[3]
Bakker, H.; Kleczka, B.; Gerardy-Schahn, R.; Routier, F.H. Identification and partial characterization of two eukaryotic UDP-galactopyranose mutases. Biol. Chem., 2005, 386(7), 657-661.
[http://dx.doi.org/10.1515/BC.2005.076] [PMID: 16207086]
[http://dx.doi.org/10.1515/BC.2005.076] [PMID: 16207086]
[4]
Richards, M.R.; Lowary, T.L. Chemistry and biology of galactofuranose-containing polysaccharides. ChemBioChem, 2009, 10(12), 1920-1938.
[http://dx.doi.org/10.1002/cbic.200900208] [PMID: 19591187]
[http://dx.doi.org/10.1002/cbic.200900208] [PMID: 19591187]
[5]
Weston, A.; Stern, R.J.; Lee, R.E.; Nassau, P.M.; Monsey, D.; Martin, S.L.; Scherman, M.S.; Besra, G.S.; Duncan, K.; McNeil, M.R. Bio-synthetic origin of mycobacterial cell wall galactofuranosyl residues. Tuber. Lung Dis., 1997, 78(2), 123-131.
[http://dx.doi.org/10.1016/S0962-8479(98)80005-1] [PMID: 9692181]
[http://dx.doi.org/10.1016/S0962-8479(98)80005-1] [PMID: 9692181]
[6]
Soltero-Higgin, M.; Carlson, E.E.; Phillips, J.H.; Kiessling, L.L. Identification of inhibitors for UDP-galactopyranose mutase. J. Am. Chem. Soc., 2004, 126(34), 10532-10533.
[http://dx.doi.org/10.1021/ja048017v] [PMID: 15327298]
[http://dx.doi.org/10.1021/ja048017v] [PMID: 15327298]
[7]
Mdluli, K.; Kaneko, T.; Upton, A. The tuberculosis drug discovery and development pipeline and emerging drug targets. Cold Spring Harb. Perspect. Med., 2015, 5(6), a021154-a021159.
[http://dx.doi.org/10.1101/cshperspect.a021154] [PMID: 25635061]
[http://dx.doi.org/10.1101/cshperspect.a021154] [PMID: 25635061]
[8]
Global TB Report (2019), WHO: Geneva, Switzerland Available
from: https://apps.who.int/iris/bitstream/handle/10665/329368/
9789241565714-eng.pdf?ua=1
[9]
Kapitonov, D.; Yu, R.K. Conserved domains of glycosyltransferases. Glycobiology, 1999, 9(10), 961-978.
[http://dx.doi.org/10.1093/glycob/9.10.961] [PMID: 10521532]
[http://dx.doi.org/10.1093/glycob/9.10.961] [PMID: 10521532]
[10]
Pedersen, L.L.; Turco, S.J. Galactofuranose metabolism: A potential target for antimicrobial chemotherapy. Cell. Mol. Life Sci., 2003, 60(2), 259-266.
[http://dx.doi.org/10.1007/s000180300021] [PMID: 12678491]
[http://dx.doi.org/10.1007/s000180300021] [PMID: 12678491]
[11]
Gschwend, D.A.; Good, A.C.; Kuntz, I.D. Molecular docking towards drug discovery. J. Mol. Recognit., 1996, 9(2), 175-186.
[http://dx.doi.org/10.1002/(SICI)1099-1352(199603)9:2<175:AID-JMR260>3.0.CO;2-D] [PMID: 8877811]
[http://dx.doi.org/10.1002/(SICI)1099-1352(199603)9:2<175:AID-JMR260>3.0.CO;2-D] [PMID: 8877811]
[12]
Goodsell, D.S.; Morris, G.M.; Olson, A.J. Automated docking of flexible ligands: Applications of AutoDock. J. Mol. Recognit., 1996, 9(1), 1-5.
[http://dx.doi.org/10.1002/(SICI)1099-1352(199601)9:1<1:AID-JMR241>3.0.CO;2-6] [PMID: 8723313]
[http://dx.doi.org/10.1002/(SICI)1099-1352(199601)9:1<1:AID-JMR241>3.0.CO;2-6] [PMID: 8723313]
[13]
Cosconati, S.; Forli, S.; Perryman, A.L.; Harris, R.; Goodsell, D.S.; Olson, A.J. Virtual screening with AutoDock: Theory and practice. Expert Opin. Drug Discov., 2010, 5(6), 597-607.
[http://dx.doi.org/10.1517/17460441.2010.484460] [PMID: 21532931]
[http://dx.doi.org/10.1517/17460441.2010.484460] [PMID: 21532931]
[14]
Irwin, J.J.; Shoichet, B.K. ZINC-a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model., 2005, 45(1), 177-182.
[http://dx.doi.org/10.1021/ci049714+] [PMID: 15667143]
[http://dx.doi.org/10.1021/ci049714+] [PMID: 15667143]
[15]
Formica, J.V.; Regelson, W. Review of the biology of Quercetin and related bioflavonoids. Food Chem. Toxicol., 1995, 33(12), 1061-1080.
[http://dx.doi.org/10.1016/0278-6915(95)00077-1] [PMID: 8847003]
[http://dx.doi.org/10.1016/0278-6915(95)00077-1] [PMID: 8847003]
[16]
González, R.; Ballester, I.; López-Posadas, R.; Suárez, M.D.; Zarzuelo, A.; Martínez-Augustin, O.; Sánchez de Medina, F. Effects of flavo-noids and other polyphenols on inflammation. Crit. Rev. Food Sci. Nutr., 2011, 51(4), 331-362.
[http://dx.doi.org/10.1080/10408390903584094] [PMID: 21432698]
[http://dx.doi.org/10.1080/10408390903584094] [PMID: 21432698]
[17]
de Groot, H.; Rauen, U. Tissue injury by reactive oxygen species and the protective effects of flavonoids. Fundam. Clin. Pharmacol., 1998, 12(3), 249-255.
[http://dx.doi.org/10.1111/j.1472-8206.1998.tb00951.x] [PMID: 9646056]
[http://dx.doi.org/10.1111/j.1472-8206.1998.tb00951.x] [PMID: 9646056]
[18]
Kuppusamy, A.; Arumugam, M.; George, S. Combining in silico and in vitro approaches to evaluate the acetylcholinesterase inhibitory profile of some commercially available flavonoids in the management of Alzheimer’s disease. Int. J. Biol. Macromol., 2017, 95, 199-203.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.11.062] [PMID: 27871793]
[http://dx.doi.org/10.1016/j.ijbiomac.2016.11.062] [PMID: 27871793]
[19]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Auto-mated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[20]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permea-bility in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[21]
Lipinski, C.A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods, 2000, 44(1), 235-249.
[http://dx.doi.org/10.1016/S1056-8719(00)00107-6] [PMID: 11274893]
[http://dx.doi.org/10.1016/S1056-8719(00)00107-6] [PMID: 11274893]
[22]
Madeswaran, A.; Asokkumar, K. Evaluation of inhibitory affinity potential of the alkaloids against crystal structure of human angiotensin-converting enzyme using Lamarckian genetic algorithm. Orient. Pharm. Exp. Med., 2015, 15(3), 183-189.
[http://dx.doi.org/10.1007/s13596-015-0188-4]
[http://dx.doi.org/10.1007/s13596-015-0188-4]
[23]
Mitrasinovic, P.M. Advances in the structure-based design of the influenza A neuraminidase inhibitors. Curr. Drug Targets, 2010, 11(3), 315-326.
[http://dx.doi.org/10.2174/138945010790711932] [PMID: 20210756]
[http://dx.doi.org/10.2174/138945010790711932] [PMID: 20210756]
[24]
Madeswaran, A. Computational evaluation of certain flavonoids against poly (ADP-Ribose) Polymerase-1 using in silico docking studies. Int. J. Phytopharmacol., 2019, 9(1), 1-6.
[25]
Benet, L.Z.; Hosey, C.M.; Ursu, O.; Oprea, T.I. BDDCS, the rule of 5 and drugability. Adv. Drug Deliv. Rev., 2016, 101, 89-98.
[http://dx.doi.org/10.1016/j.addr.2016.05.007] [PMID: 27182629]
[http://dx.doi.org/10.1016/j.addr.2016.05.007] [PMID: 27182629]
[26]
Chen, X.; Li, H.; Tian, L.; Li, Q.; Luo, J.; Zhang, Y. Analysis of the physicochemical properties of acaricides based on lipinski’s rule of five. J. Comput. Biol., 2020, 27(9), 1397-1406.
[http://dx.doi.org/10.1089/cmb.2019.0323] [PMID: 32031890]
[http://dx.doi.org/10.1089/cmb.2019.0323] [PMID: 32031890]
[27]
Lowary, T.L.; Li, J. Synthesis and evaluation of bicycle [3.1.0] hexane-based UDP-Galf analogues as inhibitors of the mycobacterial galactofuranosyltransferase GlfT2. Molecules, 2016, 21(8), 1053-1058.
[http://dx.doi.org/10.3390/molecules21081053] [PMID: 27529206]
[http://dx.doi.org/10.3390/molecules21081053] [PMID: 27529206]
[28]
Nassau, P.M.; Martin, S.L.; Brown, R.E.; Weston, A.; Monsey, D.; McNeil, M.R.; Duncan, K. Galactofuranose biosynthesis in Escherichia coli K-12: identification and cloning of UDP-galactopyranose mutase. J. Bacteriol., 1996, 178(4), 1047-1052.
[http://dx.doi.org/10.1128/jb.178.4.1047-1052.1996] [PMID: 8576037]
[http://dx.doi.org/10.1128/jb.178.4.1047-1052.1996] [PMID: 8576037]
[29]
Meniche, X.; Otten, R.; Siegrist, M.S.; Baer, C.E.; Murphy, K.C.; Bertozzi, C.R.; Sassetti, C.M. Subpolar addition of new cell wall is di-rected by DivIVA in mycobacteria. Proc. Natl. Acad. Sci. USA, 2014, 111(31), E3243-E3251.
[http://dx.doi.org/10.1073/pnas.1402158111] [PMID: 25049412]
[http://dx.doi.org/10.1073/pnas.1402158111] [PMID: 25049412]
[30]
Ota, R.; Okamoto, Y.; Vavricka, C.J.; Oka, T.; Matsunaga, E.; Takegawa, K.; Kiyota, H.; Izumi, M. Chemo-enzymatic synthesis of p-nitrophenyl β-D-galactofuranosyl disaccharides from Aspergillus sp. fungal-type galactomannan. Carbohydr. Res., 2019, 473, 99-103.
[http://dx.doi.org/10.1016/j.carres.2019.01.005] [PMID: 30658252]
[http://dx.doi.org/10.1016/j.carres.2019.01.005] [PMID: 30658252]
Article Metrics
14
1