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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

General Research Article

Design of Novel Drug-like Molecules Using Informatics Rich Secondary Metabolites Analysis of Indian Medicinal and Aromatic Plants

Author(s): Divya Karade, Durairaj Vijayasarathi, Narendra Kadoo, Renu Vyas, P.K. Ingle and Muthukumarasamy Karthikeyan*

Volume 23 , Issue 10 , 2020

Page: [1113 - 1131] Pages: 19

DOI: 10.2174/1386207323666200606211342

Price: $65

Abstract

Background: Several medicinal plants are being used in Indian medicine systems from ancient times. However, in most cases, the specific molecules or the active ingredients responsible for the medicinal or therapeutic properties are not yet known.

Objective: This study aimed to report a computational protocol as well as a tool for generating novel potential drug candidates from the bioactive molecules of Indian medicinal and aromatic plants through the chemoinformatics approach.

Methods: We built a database of the Indian medicinal and aromatic plants coupled with associated information (plant families, plant parts used for the medicinal purpose, structural information, therapeutic properties, etc.) We also developed a Java-based chemoinformatics open-source tool called DoMINE (Database of Medicinally Important Natural products from plantaE) for the generation of virtual library and screening of novel molecules from known medicinal plant molecules. We employed chemoinformatics approaches to in-silico screened metabolites from 104 Indian medicinal and aromatic plants and designed novel drug-like bioactive molecules. For this purpose, 1665 ring containing molecules were identified by text mining of literature related to the medicinal plant species, which were later used to extract 209 molecular scaffolds. Different scaffolds were further used to build a focused virtual library. Virtual screening was performed with cluster analysis to predict drug-like and lead-like molecules from these plant molecules in the context of drug discovery. The predicted drug-like and lead-like molecules were evaluated using chemoinformatics approaches and statistical parameters, and only the most significant molecules were proposed as the candidate molecules to develop new drugs.

Results and Conclusion: The supra network of molecules and scaffolds identifies the relationship between the plant molecules and drugs. Cluster analysis of virtual library molecules showed that novel molecules had more pharmacophoric properties than toxicophoric and chemophoric properties. We also developed the DoMINE toolkit for the advancement of natural product-based drug discovery through chemoinformatics approaches. This study will be useful in developing new drug molecules from the known medicinal plant molecules. Hence, this work will encourage experimental organic chemists to synthesize these molecules based on the predicted values. These synthesized molecules need to be subjected to biological screening to identify potential molecules for drug discovery research.

Keywords: Medicinal plants, metabolites, text mining, drugs, scaffolds, virtual libraries, virtual screening.

[1]
(a)Yoo, I.; Alafaireet, P.; Marinov, M.; Pena-Hernandez, K.; Gopidi, R.; Chang, J-F.; Hua, L. Data mining in healthcare and biomedicine: a survey of the literature. J. Med. Syst, 2012, 36(4), 2431-2448.
[http://dx.doi.org/10.1007/s10916-011-9710-5] [PMID: 21537851]
(b)Kostoff, R.N. Method for data and text mining and literaturebased discovery; U.S. Patent 6886010,2005.
[2]
Bellis, L.J.; Akhtar, R.; Al-Lazikani, B.; Atkinson, F.; Bento, A.P.; Chambers, J.; Davies, M.; Gaulton, A.; Hersey, A.; Ikeda, K. Collation and Data-Mining of Literature Bioactivity Data for Drug Discovery; Portland Press Limited, 2011.
[http://dx.doi.org/10.1042/BST0391365]
[3]
(a)Samal, J. Role of AYUSH workforce, therapeutics, and principles in health care delivery with special reference to National Rural Health Mission. Ayu, 2015, 36(1), 5-8.
[http://dx.doi.org/10.4103/0974-8520.169010] [PMID: 26730131] (b)Samal, J. Situational analysis and future directions of AYUSH: An assessment through 5-year plans of India. J. Intercult. Ethnopharmacol., 2015, 4(4), 348-354.
[http://dx.doi.org/10.5455/jice.20151101093011] [PMID: 26649240]
[4]
Kala, C.P.; Dhyani, P.P.; Sajwan, B.S. Developing the medicinal plants sector in northern India: challenges and opportunities. J. Ethnobiol. Ethnomed., 2006, 2(1), 32.
[http://dx.doi.org/10.1186/1746-4269-2-32]
[5]
Shiva, M. Inventory of Forest Resources for Sustainable Management & Biodiversity Conservation with Lists of Multipurpose Tree Species Yielding Both Timber & Non-timber Forest Products (NTFPs), and Shrub & Herb Species of NTFP Importance; Indus Publishing, 1998.
[6]
Chauhan, N.S. Medicinal and aromatic plants of Himachal Pradesh; Indus publishing, 1999.
[7]
Wojdyło, A.; Oszmiański, J.; Czemerys, R. Antioxidant activity and phenolic compounds in 32 selected herbs. Food Chem., 2007, 105(3), 940-949.
[http://dx.doi.org/10.1016/j.foodchem.2007.04.038]
[8]
Raut, J.S.; Karuppayil, S.M. A status review on the medicinal properties of essential oils. Ind. Crops Prod., 2014, 62, 250-264.
[http://dx.doi.org/10.1016/j.indcrop.2014.05.055]
[9]
Verma, P.; Mathur, A.K.; Jain, S.P.; Mathur, A. In vitro conservation of twenty-three overexploited medicinal plants belonging to the Indian sub continent. ScientificWorldJournal, 2012, 2012929650
[10]
Karthikeyan, M.; Nimje, D.; Pahujani, R.; Tyagi, K.; Bapat, S.; Vyas, R.; Pillai Padmakumar, K. Chemoinformatics approach for building molecular networks from marine organisms. Comb. Chem. High Throughput Screen., 2015, 18(7), 673-684.
[http://dx.doi.org/10.2174/1386207318666150703112950] [PMID: 26138570]
[11]
Polur, H.; Joshi, T.; Workman, C.T.; Lavekar, G.; Kouskoumvekaki, I. Back to the roots: prediction of biologically active natural products from ayurveda traditional medicine. Mol. Inform., 2011, 30(2-3), 181-187.
[http://dx.doi.org/10.1002/minf.201000163] [PMID: 27466772]
[12]
Sen, S.; Chakraborty, R. Traditional Knowledge Digital Library: a distinctive approach to protect and promote Indian indigenous medicinal treasure. Curr. Sci., 2014, 106(10), 1340-1343.
[13]
Mohanraj, K.; Karthikeyan, B.S.; Vivek-Ananth, R.; Chand, R.B.; Aparna, S.; Mangalapandi, P.; Samal, A. IMPPAT: A curated database of Indian medicinal plants, phytochemistry and therapeutics. Sci. Rep., 2018, 8, Article Number 4329.
[14]
Pathania, S.; Ramakrishnan, S.M.; Bagler, G. Phytochemica: a platform to explore phytochemicals of medicinal plants. Database , 2015, 2015bav075
[http://dx.doi.org/10.1093/database/bav075]
[15]
Bhat, K. Medicinal and plant information databases; Medicinal Plants for Forests Conservation and Health Care, 1997.
[16]
Wishart, D.S.; Feunang, Y.D.; Guo, A.C.; Lo, E.J.; Marcu, A.; Grant, J.R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; Assempour, N.; Iynkkaran, I.; Liu, Y.; Maciejewski, A.; Gale, N.; Wilson, A.; Chin, L.; Cummings, R.; Le, D.; Pon, A.; Knox, C.; Wilson, M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res., 2018, 46(D1), D1074-D1082.
[http://dx.doi.org/10.1093/nar/gkx1037] [PMID: 29126136]
[17]
Wei, C-H.; Kao, H-Y.; Lu, Z. PubTator: a web-based text mining tool for assisting biocuration.Nucleic Acids Res., 2013, 41(Web Server issue)(W518-22)
[http://dx.doi.org/10.1093/nar/gkt441] [PMID: 23703206]
[18]
(a)Karthikeyan, M.; Pandit, D.; Vyas, R. ChemScreener: A distributed computing tool for scaffold based virtual screening.Comb. Chem. High Throughput Screen., 2015, 18(6), 544-561.
[http://dx.doi.org/10.2174/1386207318666150703112242 ] [PMID: 26138574 ]
(b)Karthikeyan, M.; Vyas, R. Chemoinformatics approach for the design and screening of focused virtual libraries. Practical Chemoinformatics; Springer, 2014, pp. 93-131.
[http://dx.doi.org/10.1007/978-81-322-1780-0_2]
[19]
Sood, A.; Ghosh, A. Literature search using PubMed: an essential tool for practicing evidence-based medicine.Journal Association of Physicians of India, 2006, 54(R), 303.
[20]
Weber, L. JChem Base-ChemAxon. Chemistry World, 2008, 5(10), 65-66.
[21]
ChemicalComputingGroup M., Molecular Operating Environment., 2008.
[22]
Ross, K.; Mazza, G. Characteristics of lignin from flax shives as affected by extraction conditions. Int. J. Mol. Sci., 2010, 11(10), 4035-4050.
[http://dx.doi.org/10.3390/ijms11104035] [PMID: 21152318]
[23]
Robert, A.; Wither, P.; Statisti, X.L. version 1.8, a powerful statistics and statistical analysis add-in for Microsoft Excel. Washington DC, , 2007.
[24]
Zloh, M.; Samaras, E.G.; Calvo-Castro, J.; Guirguis, A.; Stair, J.L.; Kirton, S.B. Drowning in diversity? A systematic way of clustering and selecting a representative set of new psychoactive substances. RSC Advances, 2017, 7(84), 53181-53191.
[http://dx.doi.org/10.1039/C7RA09066H]
[25]
Gogte, V.M. Ayurvedic Pharmacology and Therapeutic Uses of Medicinal Plants; Chaukhambha Publications, 2000.
[26]
Parasuraman, S.; Thing, G.S.; Dhanaraj, S.A. Polyherbal formulation: Concept of ayurveda. Pharmacogn. Rev., 2014, 8(16), 73-80.
[http://dx.doi.org/10.4103/0973-7847.134229] [PMID: 25125878]
[27]
(a)Glatstein, M.; Danino, D.; Wolyniez, I.; Scolnik, D. Seizures caused by ingestion of Atropa belladonna in a homeopathic medicine in a previously well infant: case report and review of the literature.. Am. J. Ther, 2014, 21(6)e196-e198
[http://dx.doi.org/10.1097/MJT.0b013e3182785eb7] [PMID: 24105354]
(b)Panda, A.K.; Debnath, S.K. Overdose effect of aconite containing Ayurvedic Medicine (‘Mahashankha Vati’). Int. J. Ayurveda Res., 2010, 1(3), 183-186.
[http://dx.doi.org/10.4103/0974-7788.72493] [PMID: 21170213]
[28]
Boros, B.; Farkas, A.; Jakabová, S.; Bacskay, I.; Kilár, F.; Felinger, A. LC-MS quantitative determination of atropine and scopolamine in the floral nectar of Datura species. Chromatographia, 2010, 71(1), 43-49.
[http://dx.doi.org/10.1365/s10337-010-1524-y]
[29]
(a)Khan, A.V.; Ahmed, Q.U.; Khan, M.W.; Khan, A.A. Herbal cure for poisons and poisonous bites from Western Uttar Pradesh, India. Asian Pac. J. Trop. Dis., 2014, 4, S116-S120.
[http://dx.doi.org/10.1016/S2222-1808(14)60425-4]
(b)Scarpa, A.; Guerci, A. Various uses of the castor oil plant (Ricinus communis L.). A review. J. Ethnopharmacol., 1982, 5(2), 117-137.
[http://dx.doi.org/10.1016/0378-8741(82)90038-1] [PMID: 7035750]
[30]
Wachira, S.W.; Omar, S.; Jacob, J.W.; Wahome, M.; Alborn, H.T.; Spring, D.R.; Masiga, D.K.; Torto, B. Toxicity of six plant extracts and two pyridone alkaloids from Ricinus communis against the malaria vector Anopheles gambiae. Parasit. Vectors, 2014, 7(1), 312.
[http://dx.doi.org/10.1186/1756-3305-7-312] [PMID: 24996560]
[31]
Duarte, M.C.; Rai, M. Therapeutic Medicinal Plants: From Lab to the Market; CRC Press, 2015.
[http://dx.doi.org/10.1201/b19773]
[32]
Jiang, H.; Zheng, G.; Lv, J.; Chen, H.; Lin, J.; Li, Y.; Fan, G.; Ding, X. Identification of Centella asiatica’s Effective Ingredients for Inducing the Neuronal Differentiation. Evidence Based Complementary and Alternative Medicine., 2016, 2016, 1-9.
[33]
Augusti, K.T. Therapeutic values of onion (Allium cepa L.) and garlic (Allium sativum L.). Indian J. Exp. Biol., 1996, 34(7), 634-640.
[PMID: 8979497]
[34]
(a)Vlase, L.; Parvu, M.; Parvu, E.A.; Toiu, A. Chemical constituents of three Allium species from Romania.Molecules, 2012, 18(1), 114-127.
[http://dx.doi.org/10.3390/molecules18010114] [PMID: 23344191]
(b)Martins, N.; Petropoulos, S.; Ferreira, I.C. Chemical composition and bioactive compounds of garlic (Allium sativum L.) as affected by pre- and post-harvest conditions: A review. Food Chem., 2016, 211, 41-50.
[http://dx.doi.org/10.1016/j.foodchem.2016.05.029] [PMID: 27283605]
[35]
Pacirc, M.; Pacirc, A.E.; Roşca-Casian, O.; Vlase, L.; Groza, G. Antifungal activity of Allium obliquum. J. Med. Plants Res., 2010, 4(2), 138-141.
[36]
Mishra, R.K.; Kumar, A.; Kumar, A. Pharmacological activity of Zingiber officinale. Int. J. Chem. Pharm. Anal., 2012, 1(3), 1073-1078.
[37]
Uddin, Q.; Samiulla, L.; Singh, V.; Jamil, S. Phytochemical and pharmacological profile of Withania somnifera Dunal: a review. J. Appl. Pharm. Sci., 2012, 2(01), 170-175.
[38]
Harikarnpakdee, S.; Chuchote, C. Oviposition deterrent efficacy and characteristics of a botanical natural product, Ocimum gratissimum (L.) oil-alginate beads, against Aedes aegypti (L.). ScientificWorldJournal, 2018, 20183127214
[http://dx.doi.org/10.1155/2018/3127214] [PMID: 30154681]
[39]
Lagunin, A.A.; Goel, R.K.; Gawande, D.Y.; Pahwa, P.; Gloriozova, T.A.; Dmitriev, A.V.; Ivanov, S.M.; Rudik, A.V.; Konova, V.I.; Pogodin, P.V.; Druzhilovsky, D.S.; Poroikov, V.V. Chemo- and bioinformatics resources for in silico drug discovery from medicinal plants beyond their traditional use: a critical review. Nat. Prod. Rep., 2014, 31(11), 1585-1611.
[http://dx.doi.org/10.1039/C4NP00068D] [PMID: 25051191]
[40]
(a)Dardouri, T.; Gautier, H.; Ben Issa, R.; Costagliola, G.; Gomez, L. Repellence of Myzus persicae (Sulzer): evidence of two modes of action of volatiles from selected living aromatic plants. Pest Manag. Sci., 2019, 75(6), 1571-1584.
[http://dx.doi.org/10.1002/ps.5271] [PMID: 30461184]
(b)Khan, M.S.; Ahmad, I. In vitro antifungal, anti-elastase and anti-keratinase activity of essential oils of Cinnamomum-, Syzygium- and Cymbopogon-species against Aspergillus fumigatus and Trichophyton rubrum. Phytomedicine: international journal of phytotherapy and phytopharmacology, 2011, 19(1), 48-55.
(c)Swamy, M.K.; Sinniah, U.R. A comprehensive review on the phytochemical constituents and pharmacological activities of pogostemon cablin benth.: An aromatic medicinal plant of industrial importance. Molecules 2015, 20(5), 8521-8547.
[http://dx.doi.org/10.3390/molecules20058521] [PMID: 25985355]
(d)Padalia, R.C.; Verma, R.S.; Chauhan, A.; Goswami, P.; Chanotiya, C.S.; Saroj, A.; Samad, A.; Khaliq, A. Compositional variability and antifungal potentials of ocimum basilicum, O. tenuiflorum, O. gratissimum and O. kilimandscharicum essential oils against Rhizoctonia solani and Choanephora cucurbitarum. Nat. Prod. Commun. 2014, 9(10), 1507-1510.
[http://dx.doi.org/10.1177/1934578X1400901026] [PMID: 25522548]
(e)Du, S.S.; Yang, K.; Wang, C.F.; You, C.X.; Geng, Z.F.; Guo, S.S.; Deng, Z.W.; Liu, Z.L. Chemical constituents and activities of the essential oil from Myristica fragrans against cigarette beetle Lasioderma serricorne. Chem. Biodivers., 2014, 11(9), 1449-1456.
[http://dx.doi.org/10.1002/cbdv.201400137] [PMID: 25238085]
[41]
Thulesius, O.; Gjöres, J.E.; Berlin, E. Vasoconstrictor effect of midodrine, ST 1059, noradrenaline, etilefrine and dihydroergotamine on isolated human veins. Eur. J. Clin. Pharmacol., 1979, 16(6), 423-424.
[http://dx.doi.org/10.1007/BF00568204] [PMID: 93544]
[42]
Lee, Y.H.; Lee, K.J.; Min, Y.H.; Ahn, H.C.; Sohn, Y.D.; Lee, W.W.; Oh, Y.T.; Cho, G.C.; Seo, J.Y.; Shin, D.H.; Park, S.O.; Park, S.M. Refractory ventricular fibrillation treated with esmolol. Resuscitation, 2016, 107, 150-155.
[http://dx.doi.org/10.1016/j.resuscitation.2016.07.243] [PMID: 27523955]
[43]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1999, 1(1), 55-68.
[http://dx.doi.org/10.1021/cc9800071] [PMID: 10746014]
[44]
Singh, N.; Guha, R.; Giulianotti, M.A.; Pinilla, C.; Houghten, R.A.; Medina-Franco, J.L. Chemoinformatic analysis of combinatorial libraries, drugs, natural products, and molecular libraries small molecule repository. J. Chem. Inf. Model., 2009, 49(4), 1010-1024.
[http://dx.doi.org/10.1021/ci800426u] [PMID: 19301827]
[45]
Lee, M-L.; Schneider, G. Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. J. Comb. Chem., 2001, 3(3), 284-289.
[http://dx.doi.org/10.1021/cc000097l] [PMID: 11350252]
[46]
Torjesen, I. Drug development: the journey of a medicine from lab to shelf. The Pharmaceutical Journal, 25 June;2015
[47]
DiMasi, J.A.; Grabowski, H.G.; Hansen, R.W. Innovation in the pharmaceutical industry: New estimates of R&D costs. J. Health Econ., 2016, 47, 20-33.
[http://dx.doi.org/10.1016/j.jhealeco.2016.01.012] [PMID: 26928437]
[48]
Gordon, E.M.; Barrett, R.W.; Dower, W.J.; Fodor, S.P.; Gallop, M.A. Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions. J. Med. Chem., 1994, 37(10), 1385-1401.
[http://dx.doi.org/10.1021/jm00036a001] [PMID: 8182695]
[49]
Blondelle, S.E.; Pérez-Payá, E.; Houghten, R.A. Synthetic combinatorial libraries: novel discovery strategy for identification of antimicrobial agents. Antimicrob. Agents Chemother., 1996, 40(5), 1067-1071.
[http://dx.doi.org/10.1128/AAC.40.5.1067] [PMID: 8723442]
[50]
(a)Truchon, J.; Bayly, C. GLARE-A free open source software for combinatorial library design. J. Chem. Inf. Model., 2006, 46, 1536-1548.
[http://dx.doi.org/10.1021/ci0504871] [PMID: 16859286]
(b)Truszkowski, A.; Jayaseelan, K.V.; Neumann, S.; Willighagen, E.L.; Zielesny, A.; Steinbeck, C. New developments on the cheminformatics open workflow environment CDK-Taverna. J. Cheminform., 2011, 3(1), 54.
[http://dx.doi.org/10.1186/1758-2946-3-54] [PMID: 22166170]
(c)Schüller, A.; Hähnke, V.; Schneider, G. SmiLib v2. 0: A Java Based Tool for Rapid Combinatorial Library Enumeration. QSAR Comb. Sci., 2007, 26(3), 407-410.
[http://dx.doi.org/10.1002/qsar.200630101]
[51]
(a)Stevenson, J.M.; Mulready, P.D. Pipeline Pilot 2.1 By Scitegic, 9665 Chesapeake Drive, Suite 401, San Diego, CA; , 2003, pp. 92123-1365.
(b)Kochev, N.A.S.; Jeliazkova, N. Combinatorial Generation of Molecules by Virtual Software Reactor; Sci Work Union Sci Bulg Plovdiv, 2017, pp. 214-219.
(c)Sud, M.; Fahy, E.; Subramaniam, S. Template-based combinatorial enumeration of virtual compound libraries for lipids. J. Cheminform, 2012, 4(1), 23.
[http://dx.doi.org/10.1186/1758-2946-4-23 ] [PMID: 23006594]
(d)Buntrock, R.E. )ChemOffice Ultra 7.0. J. Chem. Inf. Comput. Sci., 2002, 42(6), 1505-1506.
[http://dx.doi.org/10.1021/ci025575p] [PMID: 12444749]
(e)Liao, C.; Liu, B.; Shi, L.; Zhou, J.; Lu, X-P. Construction of a virtual combinatorial library using SMILES strings to discover potential structure-diverse PPAR modulators. Eur. J. Med. Chem., 2005, 40(7), 632-640.
[http://dx.doi.org/10.1016/j.ejmech.2005.02.006] [PMID: 15935898]
(f)Feuston, B.P.; Chakravorty, S.J.; Conway, J.F.; Culberson, J.C.; Forbes, J.; Kraker, B.; Lennon, P.A.; Lindsley, C.; McGaughey, G.B.; Mosley, R.; Sheridan, R.P.; Valenciano, M.; Kearsley, S.K. Web enabling technology for the design, enumeration, optimization and tracking of compound libraries.Curr. Top. Med. Chem., 2005, 5(8), 773-783.
[http://dx.doi.org/10.2174/1568026054637656] [PMID: 16101417]
(g)Leach, A.R.; Bradshaw, J.; Green, D.V.; Hann, M.M.; Delany, J.J., III Implementation of a system for reagent selection and library enumeration, profiling, and design. J. Chem. Inf. Comput. Sci, 1999, 39(6), 1161-1172.
[http://dx.doi.org/10.1021/ci9904259] [PMID: 10614028]
(h)Yasri, A.; Berthelot, D.; Gijsen, H.; Thielemans, T.; Marichal, P.; Engels, M.; Hoflack, J. REALISIS: a medicinal chemistry-oriented reagent selection, library design, and profiling platform. J. Chem. Inf. Comput. Sci., 2004, 44(6), 2199-2206.
[http://dx.doi.org/10.1021/ci049879i] [PMID: 15554690]
[52]
(a)Sun, H.; Tawa, G.; Wallqvist, A. Classification of scaffold-hopping approaches.Drug Discov. Today, 2012, 17(7-8), 310-324.
[http://dx.doi.org/10.1016/j.drudis.2011.10.024] [PMID: 22056715]
(b)Martin, Y.C.; Muchmore, S. Beyond QSAR: lead hopping to different structures. QSAR Comb. Sci., 2009, 28(8), 797-801.
[http://dx.doi.org/10.1002/qsar.200810176]
[53]
Abel, U.; Koch, C.; Speitling, M.; Hansske, F.G. Modern methods to produce natural-product libraries. Curr. Opin. Chem. Biol., 2002, 6(4), 453-458.
[http://dx.doi.org/10.1016/S1367-5931(02)00338-1] [PMID: 12133720]
[54]
Karthikeyan, M.; Vyas, R. Role of open source tools and resources in virtual screening for drug discovery. Comb. Chem. High Throughput Screen., 2015, 18(6), 528-543.
[http://dx.doi.org/10.2174/1386207318666150703111911] [PMID: 26138575]

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