Virtual Screening of Henna Compounds Library for Discovery of New Leads against Human Thymidine Phosphorylase, an Overexpressed Factor of Hand-Foot Syndrome

Author(s): Davood Khodabakhshi-Javinani, Azadeh Ebrahim-Habibi*, Minoo Afshar, Latifeh Navidpour*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 6 , 2019

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Graphical Abstract:


Background: Capecitabine is one of the most effective and successful drugs for the treatment of uterine and colorectal cancer which has been limited in use due to occurrence of handfoot syndrome (HFS). Overexpression of human thymidine phosphorylase enzyme is predicted to be one of the main causes of this syndrome. Thymidine phosphorylase enzyme is involved in many cancers and inflammatory diseases and pyrimidine nucleoside phosphorylase family is found in a variety of organisms. Results of clinical studies have shown that topical usage of henna plant (Lawsonia inermis from the family of Lythraceae) could reduce the severity of HFS.

Methods: By using in silico methods on reported compounds of henna, the present study is aimed at finding phytochemicals and chemical groups with the potential to efficiently interact with and inhibit human thymidine phosphorylase. Various compounds (825) of henna from different chemical groups (138) were virtually screened by the interface to AutoDock in YASARA Software package, against the enzyme structure obtained from X-ray crystallography and refined by homology modeling methods.

Results: By virtual screening, i.e. docking of candidate ligands into the determined active site of hTP, followed by applying the scoring function of binding affinity, 71 compounds (out of 825 compounds) were estimated to have the likelihood to bind to the protein with an interaction energy higher than 10 kcal/mol (Concerning the sign of “binding energies”, please refer to the Methods section).

Conclusion: Finally, diosmetin-3'-O-β-D-glucopyranoside (#219) and monoglycosylated naphthalene were respectively selected as the most potent phytochemicals and chemical groups. Flavonoid-like compounds with appropriate interaction energy were also considered as the most probable inhibitors. More investigations on henna compounds, are needed in order to approve their effectiveness and also to explore more anti-cancer, anti-inflammatory, anti-angiogenesis and even antibiotics.

Keywords: Human thymidine phosphorylase inhibition, virtual screening, Lawsonia inermis phytochemicals, flavonoid-like compounds, hand-foot syndrome, monoglycosylated napthalene.

Livingstone, K.; Fisher, M. Diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC). Pract. Diabetes Int., 2007, 24(2), 102-106.
Alejandro, E.U.; Gregg, B.; Blandino-Rosano, M.; Cras-Meneur, C.; Bernal-Mizrachi, E. Natural history of beta-cell adaptation and failure in type 2 diabetes. Mol. Aspects Med., 2015, 42, 19-41.
De Filippis, B.; Linciano, P.; Ammazzalorso, A.; Di Giovanni, C.; Fantacuzzi, M.; Giampietro, L.; Laghezza, A.; Maccallini, C.; Tortorella, P.; Lavecchia, A.; Loiodice, F.; Amoroso, R. Structural development studies of PPARs ligands based on tyrosine scaffold. Eur. J. Med. Chem., 2015, 89, 817-825.
Brun, P.; Dean, A.; Di Marco, V.; Pathak, S.; Castagliuolo, I.; Carta, D.; Ferlin, M. Peroxisome proliferator-activated receptor-γ mediates the anti-inflammatory effect of 3-hydroxy-4-pyridinecarboxylic acid derivatives: Synthesis Boil. Evaluation, 2013, 62, 486-497.
Wang, L.; Waltenberger, B.; Pferschy-Wenzig, E-M.; Blunder, M.; Liu, X.; Malainer, C.; Blazevic, T.; Schwaiger, S.; Rollinger, J.M.; Heiss, E.H.; Schuster, D.; Kopp, B.; Bauer, R.; Stuppner, H.; Dirsch, V.M.; Atanasov, A.G. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): A review. Biochem. Pharmacol., 2014, 92(1), 73-89.
Ferreira, A.E.; Sisti, F.; Sônego, F.; Wang, S.; Filgueiras, L.; Brandt, S.; Serezani, A.P.M.; Du, H.; Cunha, F.Q.; Alves-Filho, J.C.; Serezani, C.H. PPAR-γ/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. J. Immunol., 2014, 192(5), 2357-2365.
Ye, J. Challenges in drug discovery for thiazolidinedione substitute. Yao xue xue bao. Acta. Pharmaceutica. Sinica., 2011, 1(3), 137-142.
Kouskoumvekaki, I.; Petersen, R.K.; Fratev, F.; Taboureau, O.; Nielsen, T.E.; Oprea, T.I.; Sonne, S.B.; Flindt, E.N.; Jónsdóttir, S.Ó.; Kristiansen, K. Discovery of a novel selective PPARγ ligand with partial agonist binding properties by integrated in silico/in vitro work flow. J. Chem. Inf. Model., 2013, 53(4), 923-937.
Bar-Tana, J. Peroxisome proliferator-activated receptor gamma (PPARgamma) activation and its consequences in humans. Toxicol. Lett., 2001, 120(1-3), 9-19.
Schiefelbein, D.; Seitz, O.; Goren, I.; Dißmann, J.P.; Schmidt, H.; Bachmann, M.; Sader, R.; Geisslinger, G.; Pfeilschifter, J.; Frank, S. Keratinocyte-derived vascular endothelial growth factor biosynthesis represents a pleiotropic side effect of peroxisome proliferator-activated receptor-γ agonist troglitazone but not rosiglitazone and involves activation of p38 mitogen-activated protein kinase: Implications for diabetes-impaired skin repair. Mol. Pharmacol., 2008, 74(4), 952.
Yamauchi, T.; Waki, H.; Kamon, J.; Murakami, K.; Motojima, K.; Komeda, K.; Miki, H.; Kubota, N.; Terauchi, Y.; Tsuchida, A.; Tsuboyama-Kasaoka, N.; Yamauchi, N.; Ide, T.; Hori, W.; Kato, S.; Fukayama, M.; Akanuma, Y.; Ezaki, O.; Itai, A.; Nagai, R.; Kimura, S.; Tobe, K.; Kagechika, H.; Shudo, K.; Kadowaki, T. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes. J. Clin. Invest., 2001, 108(7), 1001-1003.
Southan, C.; Sitzmann, M.; Muresan, S. Comparing the chemical structure and protein content of ChEMBL, drugbank, human metabolome database and the therapeutic target database. Mol. Inform., 2013, 32(11-12), 881-897.
Awale, M.; van Deursen, R.; Reymond, J.L. MQN-mapplet: Visualization of chemical space with interactive maps of DrugBank, ChEMBL, PubChem, GDB-11, and GDB-13. J. Chem. Inf. Model., 2013, 53(2), 509-518.
Dokuyucu, R.; Gozukara, K.H.; Ozcan, O.; Sefil, N.K.; Nacar, A.; Dokuyucu, A.; Inci, M. The effect of Bongardia Chrysogonum on prostate tissue in a rat model of STZ-induced diabetes. Springerplus, 2016, 5(1), 1322.
Zhang, M.; Lv, X-Y.; Li, J.; Xu, Z-G.; Chen, L. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Experiment. Diabetes Res., 2008, 2008, 7040-7045.
Hazman, O.; Ovali, S. Investigation of the anti-inflammatory effects of safranal on high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Inflammation, 2015, 38(3), 1012-1019.
Levers, K.; Galvan, E.; Coletta, A.; Dalton, R.; Jung, Y.; O’Connor, A.; Goodenough, C.; Simbo, S.; Seesselberg, C.; Bonin, B.; Koozehchian, M.; Sanchez, B.; Barringer, N.; Rasmussen, C.; Greenwood, M.; Kreider, R. Assessment of factors related to carbohydrate intolerance I: OGTT glucose AUC. FASEB J., 2014, 28, 1.
Alyass, A.; Almgren, P.; Akerlund, M.; Dushoff, J.; Isomaa, B.; Nilsson, P.; Tuomi, T.; Lyssenko, V.; Groop, L.; Meyre, D. Modelling of OGTT curve identifies 1 h plasma glucose level as a strong predictor of incident type 2 diabetes: Results from two prospective cohorts. Diabetologia, 2015, 58(1), 87-97.
Blasetti, F.; Usai, D.; Sotgia, S.; Carru, C.; Zanetti, S.; Pinna, A. A protocol for microbiologically safe preparation, storage, and use of autologous serum eye-drops in low-income countries. J. Infect. Dev. Countr., 2015, 9(1), 55-59.
Fischer, A.H.; Jacobson, K.A.; Rose, J.; Zeller, R. Hematoxylin and eosin staining of tissue and cell sections. C.S.H. Protocols., 2008, 2008, 4986.
Cardiff, R.D.; Miller, C.H.; Munn, R.J. Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harb. Protoc., 2014, 2014(6), 655-658.
Rubenstrunk, A.; Hanf, R.; Hum, D.W.; Fruchart, J.C.; Staels, B. Safety issues and prospects for future generations of PPAR modulators. Biochimica et. Biophysica Acta., 2007, 1771(8), 1065-1081.
Zamyatnin, A.A. Fragmentomics: A New insight into structures and functions of the natural oligopeptide diversity. Rec. Adv. Biol. Biomed., 2009, 170.
Bhalla, K.; Hwang, B.J.; Choi, J.H.; Dewi, R.; Ou, L.; McLenithan, J.; Twaddel, W.; Pozharski, E.; Stock, J.; Girnun, G.D. N-Acetylfarnesylcysteine is a novel class of peroxisome proliferator-activated receptor γ ligand with partial and full agonist activity in vitro and in vivo. J. Biol. Chem., 2011, 286(48), 41626-41635.
Perryman, A.L.; Yu, W.X.; Wang, X.; Ekins, S.; Forli, S.; Li, S.G.; Freundlich, J.S.; Tonge, P.J.; Olson, A.J. A virtual screen discovers novel, fragment-sized inhibitors of Mycobacterium tuberculosis InhA. J. Chem. Inf. Model., 2015, 55(3), 645-659.

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Article Details

Year: 2019
Page: [625 - 636]
Pages: 12
DOI: 10.2174/1570180815666180816123233
Price: $58

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