In silico targeting cysteine protease 2 of Giardia lamblia by Origanum vulgare L. flavonoids as potential inhibitors
محورهای موضوعی : Computational and Theoretical Studies Related to Different Aspects of Phytochemistry
Amir Abbas Barzegari
1
,
Milad Zare
2
,
Sepideh Parvizpour
3
1 - Department of Biology, Faculty of Basic Sciences, University of Maragheh, Maragheh, Iran
2 - Department of Biology, Faculty of Basic Sciences, University of Maragheh, Maragheh, Iran
3 - Pharmaceutical Nanotechnology Research Center, Biomedical Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
کلید واژه: Cysteine proteases, Flavonoids, Giardia lamblia, Marjoram, Molecular dockings,
چکیده مقاله :
Giardiasis, caused by Giardia lamblia, is a prevalent and problematic infection. Current treatments, such as metronidazole have some limitations. Flavonoids may possess anti-giardia properties. As CP2 (giardipain-1) plays a critical role in the parasite's pathogenicity, the present study aimed to discover if the flavonoids of marjoram can target CP2 and inhibit it. After modeling the CP2 spatial structure and obtaining the chemical structure of flavonoids, molecular docking was performed using PyRx. Subsequently, pharmacokinetics and the toxicity of flavonoids with the highest binding affinity for CP2 were investigated. Finally, molecular dynamics simulation was conducted on CP2 and the final candidate. Among marjoram flavonoids, isovitexin, cosmosiin, and apigenin 7-O-methylglucuronide exhibited the highest binding affinity for CP2. However, toxicity studies revealed that isovitexin and cosmosiin are mutagens. Therefore, only apigenin 7-O-methylglucuronide can be considered a potential drug for treating giardiasis. Nevertheless, further studies are needed to confirm this hypothesis.
Giardiasis, caused by Giardia lamblia, is a prevalent and problematic infection. Current treatments, such as metronidazole have some limitations. Flavonoids may possess anti-giardia properties. As CP2 (giardipain-1) plays a critical role in the parasite's pathogenicity, the present study aimed to discover if the flavonoids of marjoram can target CP2 and inhibit it. After modeling the CP2 spatial structure and obtaining the chemical structure of flavonoids, molecular docking was performed using PyRx. Subsequently, pharmacokinetics and the toxicity of flavonoids with the highest binding affinity for CP2 were investigated. Finally, molecular dynamics simulation was conducted on CP2 and the final candidate. Among marjoram flavonoids, isovitexin, cosmosiin, and apigenin 7-O-methylglucuronide exhibited the highest binding affinity for CP2. However, toxicity studies revealed that isovitexin and cosmosiin are mutagens. Therefore, only apigenin 7-O-methylglucuronide can be considered a potential drug for treating giardiasis. Nevertheless, further studies are needed to confirm this hypothesis.
Al-Khayri, J.M., Sahana, G.R., Nagella, P., Joseph, B.V., Alessa, F.M., Al-Mssallem, M.Q., 2022. Flavonoids as potential anti-inflammatory molecules: A review. Molecules 27(9), 2901.
Allain, T., Fekete, E., Buret, A.G., 2019. Giardia cysteine proteases: The teeth behind the smile. Trends Parasitol. 35(8), 636-648.
Alston, T.A., Abeles, R.H., 1987. Enzymatic conversion of the antibiotic metronidazole to an analog of thiamine. Arch. Biochem. Biophys. 257(2), 357-362.
Argüello-García, R., Carrero, J.C., Ortega-Pierres, M.G., 2023. Extracellular cysteine proteases of key intestinal protozoan pathogens-factors linked to virulence and pathogenicity. Int. J. Mol. Sci. 24(16).
Banerjee, P., Eckert, A.O., Schrey, A.K., Preissner, R., 2018. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. W257-W263.
Caffrey, C.R., Hansell, E., Lucas, K.D., Brinen, L.S., Alvarez Hernandez, A., Cheng, J., Gwaltney, S.L., 2nd, Roush, W.R., Stierhof, Y.D., Bogyo, M., Steverding, D., McKerrow, J.H., 2001. Active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of Trypanosoma brucei rhodesiense. Mol. Biochem. Parasitol. 118(1), 61-73.
Calzada, F., Meckes, M., Cedillo-Rivera, R., 1999. Antiamoebic and antigiardial activity of plant flavonoids. Planta Med. 65(01), 78-80.
Camilo, C.J., Alves Nonato, C.D.F., Galvão-Rodrigues, F.F., Costa, W.D., Clemente, G.G., Sobreira Macedo, M.A.C., Galvão Rodrigues, F.F., Da Costa, J.G.M., 2017. Acaricidal activity of essential oils: A review. Trends Phytochem. Res. 1(4), 183-198.
Carvalho, T.B.d., Oliveira-Sequeira, T.C.G., Guimarães, S., 2014. In vitro antigiardial activity of the cysteine protease inhibitor E-64. Rev. Inst. Florestal (Sao Paulo) 56(1), 43-47.
Chaudhry, N.M.A., Saeed, S., Tariq, P., 2007. Antibacterial effects of oregano (Origanum vulgare) against gram negative bacilli. Pakistan J. Bot. 39(2), 609.
Claxton, L.D., de A. Umbuzeiro, G., DeMarini, D.M., 2010. The Salmonella mutagenicity assay: The stethoscope of genetic toxicology for the 21st century. Environ. Health Perspect. 118(11), 1515-1522.
Colovos, C., Yeates, T.O., 1993. Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Sci. 2(9), 1511-1519.
Cordingley, F.T., Crawford, G.P.M., 1986. Glardla infection causes vitamin B12 deficiency. Aust. N. Z. J. Med. 16(1), 78-79.
Dallakyan, S., Olson, A. J. (2014). Small-molecule library screening by docking with PyRx. Methods Mol Biol., 243-250. Springer New York.
Davoodi, J., Abbasi-Maleki, S., 2018. Effect of Origanum vulgare hydroalcoholic extract on Giardia lamblia cysts compared with metronidazole in vitro. Iran. J. Parasitol. 13(3), 486.
Dingsdag, S.A., Hunter, N., 2017. Metronidazole: An update on metabolism, structure-cytotoxicity and resistance mechanisms. J. Antimicrob. Chemother. 73(2), 265-279.
Eisenberg, D., Lüthy, R., Bowie, J.U., 1997. VERIFY3D: Assessment of Protein Models with Three-Dimensional Profiles, Methods in Enzymology. Elsevier, pp. 396-404.
Freeman, C.D., Klutman, N.E., Lamp, K.C., 1997. Metronidazole. Drugs 54(5), 679-708.
Girard, C., Dereure, O., Blatiere, V., Guillot, B., Bessis, D., 2006. Vitamin A deficiency phrynoderma associated with chronic giardiasis. Pediatr. Dermatol. 23(4), 346-349.
Goolsby, T.A., Jakeman, B., Gaynes, R.P., 2018. Clinical relevance of metronidazole and peripheral neuropathy: A systematic review of the literature. Int. J. Antimicrob. Agents 51(3), 319-325.
Hernández-Bolio, G.I., Torres-Tapia, L.W., Moo-Puc, R., Peraza-Sánchez, S.R., 2015. Antigiardial activity of flavonoids from leaves of Aphelandra scabra. Rev. Bras. Farmacogn. 25(3), 233-237.
Kaurinovic, B., Popovic, M., Vlaisavljevic, S., Trivic, S., 2011. Antioxidant capacity of Ocimum basilicum L. and Origanum vulgare L. extracts. Molecules16(9), 7401-7414.
Kontoyianni, M., 2017. Docking and virtual screening in drug discovery. Methods Mol. Biol. 1647, 255-266.
Kordali, S., Cakir, A., Ozer, H., Cakmakci, R., Kesdek, M., Mete, E., 2008. Antifungal, phytotoxic and insecticidal properties of essential oil isolated from Turkish Origanum acutidens and its three components, carvacrol, thymol and p-cymene. Bioresour. Technol. 99(18), 8788-8795.
Laskowski, R.A., MacArthur, M.W., Moss, D.S., Thornton, J.M., 1993. PROCHECK: A program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26(2), 283-291.
Liu, J., Fu, Z., Hellman, L., Svärd, S.G., 2019. Cleavage specificity of recombinant Giardia intestinalis cysteine proteases: Degradation of immunoglobulins and defensins. Mol. Biochem. Parasitol. 227, 29-38.
Mohammad, T., Mathur, Y., Hassan, M.I., 2020. InstaDock: A single-click graphical user interface for molecular docking-based virtual high-throughput screening. Brief. Bioinform. 22(4), bbaa279.
Mohammadhosseini, M., 2016. First report on screening of the profiles of the essential oils and volatiles from the aerial parts of Marrubium persicum using classical and advanced methods prior to gas chromatographic mass spectrometric determination. J. Med. Plants By-Prod. 5(2), 169-180.
Mohammadhosseini, M., Venditti, A., Akbarzadeh, A., 2021. The genus Perovskia Kar.: Ethnobotany, chemotaxonomy and phytochemistry: A review. Toxin Rev. 40(4), 484-505.
Mohanraj, K., Karthikeyan, B.S., Vivek-Ananth, R.P., Chand, R.P.B., Aparna, S.R., Mangalapandi, P., Samal, A., 2018. IMPPAT: A curated database of Indian medicinal plants. Phytochemistry and therapeutics. Sci. Rep. 8(1), 4329-4329.
Ortega-Pierres, G., Argüello-García, R., Laredo-Cisneros, M.S., Fonseca-Linán, R., Gómez-Mondragón, M., Inzunza-Arroyo, R., Flores-Benítez, D., Raya-Sandino, A., Chavez-Munguía, B., Ventura-Gallegos, J.L., Zentella-Dehesa, A., Bermúdez-Cruz, R.M., González-Mariscal, L., 2018. Giardipain-1, a protease secreted by Giardia duodenalis trophozoites, causes junctional, barrier and apoptotic damage in epithelial cell monolayers. Int. J. Parasitol. 48(8), 621-639.
Ortega-Pierres, M.G., Argüello-García, R., 2019. Chapter four-Giardia duodenalis: Role of Secreted Molecules as Virulent Factors in the Cytotoxic Effect on Epithelial Cells, in: Ortega-Pierres, M.G. (Ed.), Advances in Parasitology. Academic Press, pp. 129-169.
Parvizpour, S., Masoudi-Sobhanzadeh, Y., Pourseif, M.M., Barzegari, A., Razmara, J., Omidi, Y., 2021. Pharmacoinformatics-based phytochemical screening for anticancer impacts of yellow sweet clover, Melilotus officinalis (Linn.) Pall. Comput. Biol. Med. 104921.
Patridge, E., Gareiss, P., Kinch, M.S., Hoyer, D., 2016. An analysis of FDA-approved drugs: Natural products and their derivatives. Drug Discov. Today 21(2), 204-207.
Quezada-Lázaro, R., Vázquez-Cobix, Y., Fonseca-Liñán, R., Nava, P., Hernández-Cueto, D.D., Cedillo-Peláez, C., López-Vidal, Y., Huerta-Yepez, S., Ortega-Pierres, M.G., 2022. The cysteine protease giardipain-1 from Giardia duodenalis contributes to a disruption of intestinal homeostasis. Int. J. Mol. Sci. 23(21).
Raies, A.B., Bajic, V.B., 2016. In silico toxicology: Computational methods for the prediction of chemical toxicity. Wiley interdisciplinary reviews. Comput. Mol. Sci. 6(2), 147-172.
Rao, D.N., Mason, R.P., 1987. Generation of nitro radical anions of some 5-nitrofurans, 2- and 5-nitroimidazoles by norepinephrine, dopamine, and serotonin. A possible mechanism for neurotoxicity caused by nitroheterocyclic drugs. Pak. J. Pharm. Sci. 262(24), 11731-11736.
Rutz, A., Sorokina, M., Galgonek, J., Mietchen, D., Willighagen, E., Gaudry, A., Graham, J.G., Stephan, R., Page, R., Vondrášek, J., Steinbeck, C., Pauli, G.F., Wolfender, J.-L., Bisson, J., Allard, P.-M., 2022. The LOTUS initiative for open knowledge management in natural products research. eLife 11, e70780.
Saeed, S., Tariq, P., 2009. Antibacterial activity of oregano (Origanum vulgare Linn.) against Gram positive bacteria. Pak. J. Pharm. Sci. 22(4), 421-425.
Sajid, M., McKerrow, J.H., 2002. Cysteine proteases of parasitic organisms. Mol. Biochem. Parasitol. 120(1), 1-21.
Salo-Ahen, O.M.H., Alanko, I., Bhadane, R., Bonvin, A.M.J.J., Honorato, R.V., Hossain, S., Juffer, A.H., Kabedev, A., Lahtela-Kakkonen, M., Larsen, A.S., Lescrinier, E., Marimuthu, P., Mirza, M.U., Mustafa, G., Nunes-Alves, A., Pantsar, T., Saadabadi, A., Singaravelu, K., Vanmeert, M., 2021. Molecular dynamics simulations in drug discovery and pharmaceutical development. Processes 9(1), 71.
Tian, W., Chen, C., Lei, X., Zhao, J., Liang, J., 2018. CASTp 3.0: Computed atlas of surface topography of proteins. Nucleic Acids Res. 46(W1), W363-W367.
Ticona, J.C., Bilbao-Ramos, P., Amesty, Á., Flores, N., Dea-Ayuela, M.A., Bazzocchi, I.L., Jiménez, I.A., 2022. Flavonoids from Piper species as promising antiprotozoal agents against giardia intestinalis. Structure-activity relationship and drug-likeness studies. Pharmaceuticals 15(11), 1386.
Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E., Berendsen, H.J., 2005. GROMACS: Fast, flexible, and free. J. Comput. Chem. 26(16), 1701-1718.
Varughese, K.I., Ahmed, F.R., Carey, P.R., Hasnain, S., Huber, C.P., Storer, A.C., 1989. Crystal structure of a papain-E-64 complex. Biochemistry 28(3), 1330-1332.
Vivancos, V., González-Alvarez, I., Bermejo, M., Gonzalez-Alvarez, M., 2018. Giardiasis: Characteristics, pathogenesis and new insights about treatment. Curr. Top. Med. Chem. 18(15), 1287-1303.
Wang, T.-Y., Li, Q., Bi, K.-S., 2018. Bioactive flavonoids in medicinal plants: Structure, activity and biological fate. Asian J. Pharm. Sci. 13(1), 12-23.
Wiederstein, M., Sippl, M.J., 2007. ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. W407-W410.
Wu, F., Zhou, Y., Li, L., Shen, X., Chen, G., Wang, X., Liang, X., Tan, M., Huang, Z., 2020. Computational approaches in preclinical studies on drug discovery and development. Front. Chem. 8, 726.
Yamashita, F., Hashida, M., 2004. In silico approaches for predicting ADME properties of drugs. Drug Metab. Pharmacokinet. 19(5), 327-338.
Yang, R., Wei, T., Goldberg, H., Wang, W., Cullion, K., Kohane, D.S., 2017. Getting drugs across biological barriers. Adv. Mater. 29(37), 1606596.
Zajaczkowski, P., Mazumdar, S., Conaty, S., Ellis, J.T., Fletcher-Lartey, S.M., 2018. Epidemiology and associated risk factors of giardiasis in a peri-urban setting in New South Wales Australia. Epidemiol. Infect. 147, e15-e15.
Zeng, X., Zhang, P., He, W., Qin, C., Chen, S., Tao, L., Wang, Y., Tan, Y., Gao, D., Wang, B., Chen, Z., Chen, W., Jiang, Y.Y., Chen, Y.Z., 2018. NPASS: Natural product activity and species source database for natural product research, discovery and tool development. Nucleic Acids Res. 46(D1), D1217-D1222.
