Generic placeholder image

Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Target Based Virtual Screening of New Leads Inhibitor against Bacterial Cell Division Protein FtsZ for the Discovery of Antibacterial Agents

Author(s): Ratish C. Mishra, Rosy Kumari, Shivani Yadav and Jaya P. Yadav*

Volume 16, Issue 2, 2020

Page: [169 - 175] Pages: 7

DOI: 10.2174/1573406415666190206233448

Price: $65


Background: Staphylococus epidermidis coagulase negative and gram positive streptococci have emerged as major nosocomial pathogens associated with the infection of implanted medical devices and dandruff on human scalp. S. epidermidis filamenting temperature-sensitive mutant Z (FtsZ) gene encoded FtsZ protein that assembles at future bacterial cell division site that forms Z-ring structure. FtsZ is a tubulin homolog protein with low sequence similarity; this makes it possible to inhibit bacterial FtsZ protein without affecting the eukaryote cell division.

Objective: In the present study, phytochemicals of Cinnamomum zeylanicum, Punica granatum and Glycyrrhiza glabra were virtually screened for their antibacterial activity against Staphylococcus epidermidis cell division protein, FtsZ.

Methods: Molecular docking method was used to investigate new lead inhibitor against bacterial cell division protein FtsZ. SwissADME and ProTox tool were used to evaluate the toxicity of the lead molecule.

Results: Molecular docking based screening confirmed that among 122 phytochemicals, β- sitosterol and glabrol showed the highest inhibitory activity against FtsZ. SwissADME tool showed β-sitosterol and glabrol as the ideal antibacterial agents.

Conclusion: Structure based drug design strategy has been broadly used to optimize antimicrobial activity of small molecule/ligand against large protein receptor of disease, causing pathogens which gives a major breakthrough in pharmaceuticals industries. The molecular docking and SwissADME tool showed that β-sitosterol and glabrol may be developed to be potential topical and sublingual antibacterial agents, respectively.

Keywords: Phytochemicals, FtsZ, S. epidermidis, antibacterial, molecular docking, MBE, ADME.

Graphical Abstract
Nguyen, T.H.; Park, M.D.; Otto, M. Host response to Staphylococcus epidermidis colonization and infections. Front. Cell. Infect. Microbiol., 2017, 7, 1-7.
Dong, Y.; Speer, C.P.; Glaser, K. Beyond sepsis: Staphylococcus epidermidis is an underestimated but significant contributor to neonatal morbidity. Virulence, 2018, 9, 621-633.
Clavaud, C.; Jourdain, R.; Bar-Hen, A.; Tichit, M.; Bouchier, C.; Pouradier, F.; El Rawadi, C.; Guillot, J.; Ménard-Szczebara, F.; Breton, L.; Latgé, J.P. Dandruff is associated with disequilibrium in the proportion of the major bacterial and fungal populations colonizing the scalp. PLoS One, 2013, 8, 1-8.
Xu, Z.; Wang, Z.; Yuan, C.; Liu, X.; Yang, F.; Wang, T.; Wang, J.; Manabe, K.; Qin, O.; Wang, X.; Zhang, Y. Dandruff is associated with the conjoined interactions between host and microorganisms. Sci. Rep., 2016, 6, 1-9.
Ballu, S. Itteboina, R.; Sivan, S.K.; Manga, V. Structural insights of Staphylococcus aureus FtsZ inhibitors through molecular docking, 3D-QSAR and molecular dynamics simulations. J. Recept. Signal Transduct., 2018, 38, 61-70.
Willemse, J.; Borst, J.W.; de Waal, E.; Bisseling, T.; van Wezel, G.P. Positive control of cell division: FtsZ is recruited by SsgB during sporulation of Streptomyces. Genes Dev., 2011, 25, 89-99.
Uniprot, K.B. “Search by Q5HQ06”: Available at (Accessed April 15, 2018).
Schaffner-Barbero, C.; Martín-Fontecha, M.; Chacón, P.; Andreu, J.M. Targeting the assembly of bacterial cell division protein FtsZ with small molecules. ACS Chem. Biol., 2011, 7, 269-277.
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
Yelin, I.; Kishony, R. Antibiotic resistance. Cell, 2018, 172, 1136-1136.e1.
Chandra, H.; Bishnoi, P.; Yadav, A.; Patni, B.; Mishra, A.P. autiyal, A.R. Antimicrobial resistance and the alternative resources with special emphasis on plant-based antimicrobials—A review. Plants, 2017, 6, 16.
Anand, V.; Kumar, S.; Hedina, A. Cinnamomum zeylanicum Linn. The spice with multi potential. Sys. Rev. Pharm, 2016, 7, 24-29.
Al-Huqail, A.A.; Elgaaly, G.A.; Ibrahim, M.M. Identification of bioactive phytochemical from two Punica species using GC–MS and estimation of antioxidant activity of seed extracts. Saudi J. Biol. Sci., 2018, 25, 1420-1428.
Farag, M.A.; Porzel, A.; Wessjohann, L.A. Comparative metabolite profiling and fingerprinting of medicinal licorice roots using a multiplex approach of GC–MS, LC–MS and 1D NMR techniques. Phytochemistry, 2012, 76, 60-72.
Julianti, E.; Rajah, K.K.; Fidrianny, I. Antibacterial activity of ethanolic extract of Cinnamon bark, honey, and their combination effects against acne-causing bacteria. Sci. Pharm., 2017, 85, 1-8.
Abdollahzadeh, S.H.; Mashouf, R.Y.; Mortazavi, H.; Moghaddam, M.H.; Roozbahani, N.; Vahedi, M. Antibacterial and antifungal activities of Punica granatum peel extracts against oral pathogens. J. Dent., 2011, 8, 1-6.
Rezazadeh, T.; Jafarzadeh, M.; Karimi, A. Evaluation of antibacterial activity and synergistic effect between tea tree oil (Melaleuca alternifolia), burdock (Aractium lappal) and licorice (Glycyrrhiza glabra) root extract against Propionibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis. Int. J. Biol. Pharm. Allied Sci., 2017, 6, 1372-1383.
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30, 2785-2791.
Vijayalakshmi, P.; Nisha, J.; Rajalakshmi, M. Virtual screening of potential inhibitor against FtsZ protein from Staphylococcus aureus. Interdiscip. Sci. Comput. Life Sci, 2014, 6, 331-339.
Drwal, M.N.; Banerjee, P.; Dunkel, M.; Wettig, M.R.; Preissner, R. ProTox: a web server for the in silico prediction of rodent oral toxicity. Nucleic Acids Res., 2014, 42, W53-W58.
Mishra, R.C.; Kumari, R.; Yadav, J.P. Comparative study of antidandruff efficacy of Punica granatum peel and its biosynthesized silver nanoparticles. J. Bionanosci., 2018, 12, 508-514.
Center for Structural Genomics of Infectious Diseases “Search by structure/title”, Available at. (Accessed April 12, 2018).
Hemaiswarya, S.; Soudaminikkutty, R.; Narasumani, M.L.; Doble, M. Phenylpropanoids inhibit protofilament formation of Escherichia coli cell division protein FtsZ. J. Med. Microbiol., 2011, 60, 1317-1325.
Sun, N.; Chan, F.Y.; Lu, Y.J.; Neves, M.A.; Lui, H.K.; Wang, Y.; Chow, K.Y.; Chan, K.F.; Yan, S.C.; Leung, Y.C.; Abagyan, R. Rational design of berberine-based FtsZ inhibitors with broad-spectrum antibacterial activity. PLoS One, 2014, 9, 1-10.
Kumar, S.; Mawlong, I.; Singh, D. Phytosterol recovery from oilseeds: Recent advances. J. Food Process Eng., 2017, 40e12466
Edilu, A.; Adane, L.; Woyessa, D. In vitro antibacterial activities of compounds isolated from roots of Caylusea abyssinica. Ann. Clin. Microbiol. Antimicrob., 2015, 14, 1-8.
Gupta, M.B.; Nath, R.; Srivastava, N.; Shanker, K.; Kishor, K.; Bhargava, K.P. Anti-inflammatory and antipyretic activities of β-sitosterol. Planta Med., 1980, 39, 157-163.
Raicht, R.F.; Cohen, B.I.; Fazzini, E.P.; Sarwal, A.N.; Takahashi, M. Protective effect of plant sterols against chemically induced colon tumors in rats. Cancer Res., 1980, 40, 403-405.
Rajavel, T.; Packiyaraj, P.; Suryanarayanan, V.; Singh, S.K.; Ruckmani, K.; Devi, K.P. β-Sitosterol targets Trx/Trx1 reductase to induce apoptosis in A549 cells via ROS mediated mitochondrial dysregulation and p53 activation. Sci. Rep., 2018, 8, 1-15.
Bin Sayeed, M.S.; Karim, S.M.; Sharmin, T.; Morshed, M.M. Critical analysis on characterization, systemic effect, and therapeutic potential of beta-sitosterol: A plant-derived orphan phytosterol. Medicines, 2016, 3, 1-25.
Ibrahim, N.; Yaacob, W.A. Transcriptome analysis of methicillin-resistant Staphylococcus aureus in response to stigmasterol and lupeol. J. Glob. Antimicrob. Resist., 2017, 8, 48-54.
Sen, A.; Dhavan, P.; Shukla, K.K.; Singh, S.; Tejovathi, G. Analysis of IR, NMR and antimicrobial activity of β-sitosterol isolated from Momordica charantia. Sci. Secure J. Biotechnol, 2012, 1, 9-13.
Hoskeri, J.; Krishna, H.; Jignesh, V.; Roshan, S.; Vijay, S. In-silico drug designing using β-sitosterol isolated from Flaveria trinervia against peptide deformylase protein to hypothesize bactericidal effect. Int. J. Pharm. Pharm. Sci., 2012, 4, 192-196.
Ododo, M.M.; Choudhury, M.K.; Dekebo, A.H. Structure elucidation of β-sitosterol with antibacterial activity from the root bark of Malva parviflora. Springerplus, 2016, 5, 1-11.
Doğan, A.; Otlu, S.; Çelebi, Ö.; Aksu, P.; Sağlam, A.G.; Doğan, A.N.; Mutlu, N. An investigation of antibacterial effects of steroids. Turk. J. Vet. Anim. Sci., 2017, 41, 302-305.
Paniagua-Pérez, R.; Madrigal-Bujaidar, E.; Reyes-Cadena, S.; Molina-Jasso, D.; Gallaga, J.P.; Silva-Miranda, A.; Velazco, O.; Hernández, N.; Chamorro, G. Genotoxic and cytotoxic studies of beta-sitosterol and pteropodine in mouse. BioMed Res. Int., 2005, 2005, 242-247.
Nyamoita, M.G. Toxicity of individual and blends of pure phytoecdysteroids isolated from Vitex schiliebenii and Vitex payoffs against Anopheles gambiae ss larvae. World J. Org. Chem., 2013, 1, 1-5.
Nong, X.; Yao-jun, Y.; Yang, G.Y.; Feng-zheng, C.; Tang, M.; Wang, G. Toxicity of stigmasterol isolated from crofton weed, Eupatorium adenophorum Spreng. Against a rabbit ear mite, Psoroptes cuniculi. Pak. J. Zool., 2017, 49, 1197-1200.
Aminu, R.; Umar, I.A.; Rahman, M.A.; Ibrahim, M.A. Stigmasterol retards the proliferation and pathological features of Trypanosoma congolense infection in rats and inhibits Trypanosomal sialidase in vitro and in silico. Biomed. Pharmacother., 2017, 89, 482-489.
Vamsidhar, E.; Swamy, G.V.; Chitti, S.; Babu, P.A.; Venkatasatyanarayana, G.; Raju, A.D. Screening and docking studies of 266 compounds from 7 plant sources as antihypertensive agents. J. Comput. Sci. Syst. Biol., 2010, 3, 16-20.
Senthilraja, P.; Sahu, S.K.; Kathiresan, K. Potential of mangrove derived compounds against dihydrofolate reductase: An in-silico docking study. J. Comput. Biol. Bioinform. Res., 2012, 4, 23-27.
Choi, J.M.; Lee, E.O.; Lee, H.J.; Kim, K.H.; Ahn, K.S.; Shim, B.S.; Kim, N.I.; Song, M.C.; Baek, N.I.; Kim, S.H. Identification of campesterol from Chrysanthemum coronarium L. and its antiangiogenic activities. Phytother. Res., 2007, 21, 954-959.
Rizvi, S.; Raza, S.T.; Ahmed, F.; Ahmad, A.; Abbas, S.; Mahdi, F. The role of Vitamin E in human health and some diseases. Sultan Qaboos Univ. Med. J., 2014, 14, e157-e165.
Heidari, M.; Badri, R.; Rezaei, M.; Shushizadeh, M.R.; Reza, A. Mitochondrial protection against arsenic toxicity by a novel gamma tocopherol analogue in rat. Bull. Env. Pharmacol. Life Sci., 2015, 4, 43-55.
Pavithra, D.; Praveen, D.; Chowdary, P.R.; Aanandhi, M.V. A review on role of Vitamin E supplementation in type 2 diabetes mellitus. Drug Invent. Today, 2018, 10, 236-240.
Zhang, T.; Zhang, Y.Z.; Tao, J.S. Antibacterial constituents from Stemona sessilifolia. J. Asian Nat. Prod. Res., 2007, 9, 479-485.
Güneş, F.E. Medical use of squalene as a natural antioxidant. MUSBED, 2013, 3, 220-228.
Bindu, B.S.; Mishra, D.P.; Narayan, B. Inhibition of virulence of Staphylococcus aureus–a food borne pathogen–by squalene, a functional lipid. J. Funct. Foods, 2015, 18, 224-234.
Awa, E.P.; Ibrahim, S.; Ameh, D.A. GC/MS Analysis and antimicrobial activity of diethyl ether fraction of methanolic extract from the stem bark of Annona senegalensis Pers. Int. J. Pharm. Sci. Res., 2012, 3, 4213-4218.
Mala, R.; Celsia, A.R.; Devi, S.M.; Geerthika, S. Comparison on bactericidal and cytotoxic effect of silver nanoparticles synthesized by different methods. Iop Conf. Ser. Mater. Sci., 2017, 225, 1-11.
Anagha, K.; Manasi, D.; Priya, L.; Meera, M. Pharmacological studies of Yashtimadhu (Glycyrrhiza glabra L.) In various animal models-A review. Glob. J. Res. Med. Plants Indig. Med., 2013, 2, 152-164.
Haraguchi, H.; Yoshida, N.; Ishikawa, H.; Tamura, Y.; Mizutani, K.; Kinoshita, T. Protection of mitochondrial functions against oxidative stresses by isoflavans from Glycyrrhiza glabra. J. Pharm. Pharmacol., 2000, 52, 219-223.
Wang, Y.; Hao, M.M.; Sun, Y.; Wang, L.F.; Wang, H.; Zhang, Y.J.; Li, H.Y.; Zhuang, P.W.; Yang, Z. Synergistic promotion on tyrosinase inhibition by antioxidants. Molecules, 2018, 23, 1-13.
Zhang, L.; Chen, H.; Wang, M.; Song, X.; Ding, F.; Zhu, J.; Li, X. Effects of glabridin combined with 5-fluorouracil on the proliferation and apoptosis of gastric cancer cells. Oncol. Lett., 2018, 15, 7037-7045.
Jaudan, A.; Sharma, S.; Malek, S.N.; Dixit, A. Induction of apoptosis by pinostrobin in human cervical cancer cells: Possible mechanism of action. PLoS One, 2018, 13, 1-15.
Wang, L.; Yang, R.; Yuan, B.; Liu, Y.; Liu, C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm. Sin. B, 2015, 5, 310-315.
Singh, V.; Pal, A.; Darokar, M.P. A polyphenolic flavonoid glabridin: oxidative stress response in multidrug-resistant Staphylococcus aureus. Free Radic. Biol. Med., 2015, 87, 48-57.
Gupta, V.K.; Fatima, A.; Faridi, U.; Negi, A.S. Shanker. K.; Kumar, J.K.; Rahuja, N.; Luqman, S.; Sisodia, B.S.; Saikia, D.; Darokar, M.P. Antimicrobial potential of Glycyrrhiza glabra roots. J. Ethnopharmacol., 2008, 116, 377-380.
Choi, J.H.; Choi, J.N.; Lee, S.Y.; Lee, S.J.; Kim, K.; Kim, Y.K. Inhibitory activity of diacylglycerol acyltransferase by glabrol isolated from the roots of licorice. Arch. Pharm. Res., 2010, 33, 237-242.
Araya-Cloutier, C.; Vincken, J.P.; van de Schans, M.G.; Hageman, J.; Schaftenaar, G.; den Besten, H.M.; Gruppen, H. QSAR-based molecular signatures of prenylated (iso) flavonoids underlying antimicrobial potency against and membrane-disruption in Gram positive and Gram negative bacteria. Sci. Rep., 2018, 8, 1-14.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy