In Silico Target Identification and Molecular Docking Studies of Natural Cytotoxic Compound Borivilianoside H

Author(s): S. Dutta Gupta*, P. Kohli

Journal Name: Current Biotechnology

Volume 8 , Issue 2 , 2019

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Abstract:

Background: Borivilianoside H is a naturally occurring anti-cancer compound with known cytotoxicity against human colorectal cancer cell line (HCT-116) and human adenocarcinoma cell line (HT-29). The present study describes the pharmacophore modelling, molecular docking, and molecular dynamics simulation approaches to predict the target proteins of borivilianoside H along with its binding affinity to the selected proteins.

Methods: A 3-dimensional structure of borivilianoside H was constructed using Avogadro from its 2-D coordinates retrieved from the Pubchem Compound database. Target proteins associated with cancers were identified based on the 95% normalized fit score of PharmMapper. The crystal structures of the targets were retrieved from Protein Data Bank and molecular docking was performed with Autodock Vina 1.1.2. MD simulations were carried out via Google Cloud Platform. ADMET characteristics for borivilianoside H were determined using admetSAR web server.

Results: Among the selected 7 top-ranked target proteins, fibroblast activation protein (FAP) exhibited the highest binding affinity followed by serum albumin (ALB), bone morphogenetic protein 2 (BMP2) and kinesin-like protein 11 (KIF11). However, the best fit was found with KIF11, where both the steroidal and oligosaccharide moieties of borivilianoside H were involved in interacting with the protein cavity. KIF11 was thus found to be the most suitable target for the anti-cancer effect of borivilianoside. ADMET analysis revealed its suitability as an intravenous drug.

Conclusion: The targets predicted using this approach will serve as leads for the possible use of borivilianoside H, one of the active ingredients of Chlorophytum borivilianum as an anti-cancer drug.

Keywords: Borivilianoside H, anti-cancer drug, pharmacophore modelling, molecular dynamics, KIF-11, in silico.

[1]
Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers (Basel) 2014; 6(3): 1769-92.
[http://dx.doi.org/10.3390/cancers6031769] [PMID: 25198391]
[2]
Aljofan M, Netter HJ, Aljarbou AN, et al. Anti-hepatitis B activity of isoquinoline alkaloids of plant origin. Arch Virol 2014; 159(5): 1119-28.
[http://dx.doi.org/10.1007/s00705-013-1937-7] [PMID: 24311152]
[3]
Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016; 79(3): 629-61.
[http://dx.doi.org/10.1021/acs.jnatprod.5b01055] [PMID: 26852623]
[4]
Thakur GS, Bag M, Sanodiya BS, et al. Chlorophytum borivilianum: A white gold for biopharmaceuticals and neutraceuticals. Curr Pharm Biotechnol 2009; 10(7): 650-66.
[http://dx.doi.org/10.2174/138920109789542084] [PMID: 19751181]
[5]
Kaushik N. Saponins of Chlorophytum species. Phytochem Rev 2005; 4: 191-6.
[http://dx.doi.org/10.1007/s11101-005-2607-5]
[6]
Kumar M, Meena P, Verma S, Kumar M, Kumar A. Anti-tumour, anti-mutagenic and chemomodulatory potential of Chlorophytum borivilianum. Asian Pac J Cancer Prev 2010; 11(2): 327-34.
[PMID: 20843110]
[7]
Acharya D, Mitaine-Offer AC, Kaushik N, Miyamoto T, Paululat T, Lacaille-Dubois MA. Steroidal saponins from the roots of Chlorophytum borivilianum. Planta Med 2008; 74: PB23.
[http://dx.doi.org/10.1055/s-0028-1084368]
[8]
Man S, Gao W, Zhang Y, Huang L, Liu C. Chemical study and medical application of saponins as anti-cancer agents. Fitoterapia 2010; 81(7): 703-14.
[http://dx.doi.org/10.1016/j.fitote.2010.06.004] [PMID: 20550961]
[9]
Frenkel N, Makky A, Sudji IR, Wink M, Tanaka M. Mechanistic investigation of interactions between steroidal saponin digitonin and cell membrane models. J Phys Chem B 2014; 118(50): 14632-9.
[http://dx.doi.org/10.1021/jp5074939] [PMID: 25412206]
[10]
Chen X, Ung CY, Chen Y. Can an in silico drug-target search method be used to probe potential mechanisms of medicinal plant ingredients? Nat Prod Rep 2003; 20(4): 432-44.
[http://dx.doi.org/10.1039/b303745b] [PMID: 12964838]
[11]
Karpagam V, Sathishkumar N, Sathiyamoorthy S, et al. Identification of BACE1 inhibitors from Panax ginseng saponins-An Insilco approach. Comput Biol Med 2013; 43(8): 1037-44.
[http://dx.doi.org/10.1016/j.compbiomed.2013.05.009] [PMID: 23816176]
[12]
Gill BS. Navgeet, Kumar S. Ganoderic acid targeting multiple receptors in cancer: In silico and in vitro study. Tumour Biol 2016; 37(10): 14271-90.
[http://dx.doi.org/10.1007/s13277-016-5291-8] [PMID: 27592256]
[13]
Singla R, Jaitak V. Molecular docking simulation study of phytoestrogens from Asparagus racemosus in breast cancer progression. Int J Pharm Sci Res 2015; 6: 172-82.
[14]
Liu X, Shi Y, Deng Y, Dai R. Using molecular docking analysis to discovery Dregea sinensis Hemsl. potential mechanism of anti-cancer, anti-depression, and immunoregulation. Pharmacogn Mag 2017; 13(51): 358-62.
[http://dx.doi.org/10.4103/pm.pm_384_16] [PMID: 28839357]
[15]
Kim OT, Le MD, Trinh HX, Nong HV. In silico studies for the interaction of tumor necrosis factor-alpha (TNF-α) with different saponins from Vietnamese ginseng (Panax vietnamesis). Biophys Physicobiol 2016; 13: 173-80.
[http://dx.doi.org/10.2142/biophysico.13.0_173] [PMID: 27924272]
[16]
Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J Cheminform 2012; 4(1): 17.
[http://dx.doi.org/10.1186/1758-2946-4-17] [PMID: 22889332]
[17]
Liu X, Ouyang S, Yu B, et al. PharmMapper server: A web server for potential drug target identification using pharmacophore mapping approach. Nucleic Acids Res 2010; 38(Web Server issue): W609-14.
[http://dx.doi.org/10.1093/nar/gkq300] [PMID: 20430828]
[18]
Berman HM, Battistuz T, Bhat TN, et al. The protein data bank. Acta Crystallogr D Biol Crystallogr 2002; 58(Pt 6 No 1): 899-907.
[http://dx.doi.org/10.1107/S0907444902003451] [PMID: 12037327]
[19]
The Uniprot Consortium. UniProt: the universal protein knowledgebase. Nucleic Acids Res 2017; 45: D158-69.
[20]
Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[21]
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[PMID: 19499576]
[22]
Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004; 25(13): 1605-12.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[23]
Berendsen HJ, van der Spoel D, van Drunen R. GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 1995; 91: 43-56.
[http://dx.doi.org/10.1016/0010-4655(95)00042-E]
[24]
Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis 1997; 18(15): 2714-23.
[http://dx.doi.org/10.1002/elps.1150181505] [PMID: 9504803]
[25]
Schmid N, Eichenberger AP, Choutko A, et al. Definition and testing of the GROMOS force-field versions 54A7 and 54B7. Eur Biophys J 2011; 40(7): 843-56.
[http://dx.doi.org/10.1007/s00249-011-0700-9] [PMID: 21533652]
[26]
Schüttelkopf AW, van Aalten DM. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 2004; 60(Pt 8): 1355-63.
[http://dx.doi.org/10.1107/S0907444904011679] [PMID: 15272157]
[27]
Luo H, Liang DF, Bao MY, et al. In silico identification of potential inhibitors targeting Streptococcus mutans sortase A. Int J Oral Sci 2017; 9(1): 53-62.
[http://dx.doi.org/10.1038/ijos.2016.58] [PMID: 28358034]
[28]
Yan Y, Sardana V, Xu B, et al. Inhibition of a mitotic motor protein: where, how, and conformational consequences. J Mol Biol 2004; 335(2): 547-54.
[http://dx.doi.org/10.1016/j.jmb.2003.10.074] [PMID: 14672662]
[29]
Talapatra SK, Schüttelkopf AW, Kozielski F. The structure of the ternary Eg5-ADP-ispinesib complex. Acta Crystallogr D Biol Crystallogr 2012; 68(Pt 10): 1311-9.
[http://dx.doi.org/10.1107/S0907444912027965] [PMID: 22993085]
[30]
Wang ZM, Ho JX, Ruble JR, et al. Structural studies of several clinically important oncology drugs in complex with human serum albumin. Biochim Biophys Acta 2013; 1830(12): 5356-74.
[http://dx.doi.org/10.1016/j.bbagen.2013.06.032] [PMID: 23838380]
[31]
Cheng F, Li W, Zhou Y, et al. admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 2012; 52(11): 3099-105.
[http://dx.doi.org/10.1021/ci300367a] [PMID: 23092397]
[32]
Beck SE, Jung BH, Fiorino A, et al. Bone morphogenetic protein signaling and growth suppression in colon cancer. Am J Physiol Gastrointest Liver Physiol 2006; 291(1): G135-45.
[http://dx.doi.org/10.1152/ajpgi.00482.2005] [PMID: 16769811]
[33]
Li C, Tian ZN, Cai JP, et al. Panax ginseng polysaccharide induces apoptosis by targeting Twist/AKR1C2/NF-1 pathway in human gastric cancer. Carbohydr Polym 2014; 102: 103-9.
[http://dx.doi.org/10.1016/j.carbpol.2013.11.016] [PMID: 24507261]
[34]
Imai T, Oue N, Sentani K, et al. KIF11 is required for spheroid formation by oesophageal and colorectal cancer cells. Anticancer Res 2017; 37(1): 47-55.
[http://dx.doi.org/10.21873/anticanres.11287] [PMID: 28011472]
[35]
Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol 2005; 6(5): 322-7.
[http://dx.doi.org/10.1016/S1470-2045(05)70168-6] [PMID: 15863380]
[36]
Bekku S, Mochizuki H, Yamamoto T, Ueno H, Takayama E, Tadakuma T. Expression of carbonic anhydrase I or II and correlation to clinical aspects of colorectal cancer. Hepatogastroenterology 2000; 47(34): 998-1001.
[PMID: 11020863]
[37]
Heys SD, Walker LG, Deehan DJ, Eremin OE. Serum albumin: A prognostic indicator in patients with colorectal cancer. J R Coll Surg Edinb 1998; 43(3): 163-8.
[PMID: 9654876]
[38]
Scanlan MJ, Raj BK, Calvo B, et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci USA 1994; 91(12): 5657-61.
[http://dx.doi.org/10.1073/pnas.91.12.5657] [PMID: 7911242]
[39]
Hou T, Wang J, Li Y, Wang W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J Chem Inf Model 2011; 51(1): 69-82.
[http://dx.doi.org/10.1021/ci100275a] [PMID: 21117705]
[40]
Kumari R, Kumar R, Lynn A. Open Source Drug Discovery Consortium. g_mmpbsa--a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 2014; 54(7): 1951-62.
[http://dx.doi.org/10.1021/ci500020m] [PMID: 24850022]
[41]
Rodríguez Arcas MJ, García-Jiménez E, Martínez-Martínez F, Conesa-Zamora P. Role of CYP450 in pharmacokinetics and pharmacogenetics of antihypertensive drugs. Farm Hosp 2011; 35(2): 84-92.
[PMID: 21093338]
[42]
Kim YC, Lee JH, Kim MS, Lee NG. Effect of the saponin fraction of Panax ginseng on catecholamines in mouse brain. Arch Pharm Res 1985; 8: 45-8.
[http://dx.doi.org/10.1007/BF02897566]
[43]
Huong NTT, Murakami Y, Tohda M, Watanabe H, Matsumoto K. Social isolation stress-induced oxidative damage in mouse brain and its modulation by majonoside-R2, a Vietnamese ginseng saponin. Biol Pharm Bull 2005; 28(8): 1389-93.
[http://dx.doi.org/10.1248/bpb.28.1389] [PMID: 16079480]
[44]
Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation 2002; 105(7): 794-9.
[http://dx.doi.org/10.1161/hc0702.105124] [PMID: 11854117]
[45]
Takano M, Inui K, Okano T, Saito H, Hori R. Carrier-mediated transport systems of tetraethylammonium in rat renal brush-border and basolateral membrane vesicles. Biochim Biophys Acta 1984; 773(1): 113-24.
[http://dx.doi.org/10.1016/0005-2736(84)90556-X] [PMID: 6733090]
[46]
Desai SD, Desai DG, Kaur H. Saponins and their biological activities. Pharm Times 2009; 41: 13-6.


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Article Details

VOLUME: 8
ISSUE: 2
Year: 2019
Page: [127 - 137]
Pages: 11
DOI: 10.2174/2211550108666191112115330

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