NPCARE: database of natural products and fractional extracts for cancer regulation
© The Author(s) 2017
Received: 19 August 2016
Accepted: 28 December 2016
Published: 5 January 2017
Natural products have increasingly attracted much attention as a valuable resource for the development of anticancer medicines due to the structural novelty and good bioavailability. This necessitates a comprehensive database for the natural products and the fractional extracts whose anticancer activities have been verified.
NPCARE (http://silver.sejong.ac.kr/npcare) is a publicly accessible online database of natural products and fractional extracts for cancer regulation. At NPCARE, one can explore 6578 natural compounds and 2566 fractional extracts isolated from 1952 distinct biological species including plants, marine organisms, fungi, and bacteria whose anticancer activities were validated with 1107 cell lines for 34 cancer types. Each entry in NPCARE is annotated with the cancer type, genus and species names of the biological resource, the cell line used for demonstrating the anticancer activity, PubChem ID, and a wealth of information about the target gene or protein. Besides the augmentation of plant entries up to 743 genus and 197 families, NPCARE is further enriched with the natural products and the fractional extracts of diverse non-traditional biological resources.
NPCARE is anticipated to serve as a dominant gateway for the discovery of new anticancer medicines due to the inclusion of a large number of the fractional extracts as well as the natural compounds isolated from a variety of biological resources.
KeywordsNPCARE Natural product Fractional extract Anticancer medicine Database
Although a great deal of efforts has been devoted to the development of therapeutics for a long time, cancer represents the major reasons for human death at an increasing pace. Because the discovery of anticancer medicine lags behind the rapid increase in the pathogenesis of cancer, more than 10 million people are expected to die of cancer in 2020, which corresponds to approximately 20% of all human deaths. The difficulty in the development of anticancer medicines is well reflected in the fact that only 5% of the candidates entering clinical trials reach the approval for marketing . To promote the discovery of anticancer medicines, it is necessary to enrich the chemical and biological resources from which one can select a promising molecular scaffold as the starting point of the development.
With respect to the lead discovery, it is worth noting that natural products and their direct derivatives occupy 34% of new drugs approved over a few decades by US Food and Drug Administration (FDA) . Besides the possession of unique pharmacophores and a high degree of stereochemistry, natural products are superior to the synthetic compounds in terms of the delivery to the intracellular site of action because most of them belong to the biologically active metabolites that should be the actual substrates of membrane transport systems . Furthermore, natural products tend to have the better bioavailability than the synthetic compounds, which prevents them from being the false positives in the early stage of discovery .
Accordingly, several online databases for natural products have been constructed to provide a systematic and versatile platform for drug discovery including SuperNatural , CancerResource , NPACT , TCMSP , CancerHSP , TCMID , and Phytochemica . In addition to three dimensional structures of commercially available natural products and the interactions with the target proteins, these databases contain the pharmacological properties associated with absorption, distribution, metabolism, excretion, and toxicity (ADMET) as well as in vitro and in vivo anticancer activities. Despite the prevalence of publicly available databases, the number of the collected natural products with anticancer activity ranges from 1000 to 4000, which would be insufficient to serve as a breakthrough chemical library for lead generation. Furthermore, information is missing or very limited about the extract mixtures in the existing natural product databases although the traditional Chinese medicines have been very useful for finding the promising leads with respect to various pharmacological targets [12–14].
To provide information for a sufficient number of the natural products and the extract mixtures with anticancer activity to research communities worldwide through Open Access protocol, we construct an online database referred to as Natural Products for Cancer Regulation (NPCARE, http://silver.sejong.ac.kr/npcare). More specifically, NPCARE aims to complement and augment the public data repositories by the enrichment of the natural products and the fractional extracts isolated not only from plants but also from diverse non-traditional biological resources including marine organisms, fungi, and bacteria. NPCARE is therefore likely to serve as a comprehensive public resource from which users can select a good starting point for the discovery of anticancer medicines.
Data collection and assembly
Whenever the natural product or the extract mixture was found in the resources, we monitored the cell line used for validating the anticancer activity with respect to the cancer types classified by international classification of disease (ICD) of version 10. For each cancer type, the subtypes determined by histological classifications were also specified as exemplified by squamous cell lung cancer, big cell lung cancer, and adenocarcinoma for lung cancer. Two criteria were applied separately to confirm the presence of anticancer activity. First, the natural products and the fractional extracts were adopted as the element of NPCARE if they could inhibit the growth of cancer cell line. Each cell line used to assess the anticancer activity was hyperlinked to American type culture collection (ATCC) or National Center for Biotechnology Information (NCBI) for further information. The anticancer activity of a natural product and fractional extract was also assessed by the capability to downregulate the expressions of oncogenes or to upregulate the cancer-suppressing genes, which were implicated with the change in mRNA transcription levels. In this case, the gene names were also hyperlinked to the web pages of HUGO gene nomenclature committee (HGNC), Ensembl genome browser, UniProt knowledgebase, and catalogue of somatic mutations in cancer (COSMIC) so that users can refer to the details of the target gene. NPCARE also offers the hyperlink to PubChem for further information about the physicochemical and pharmacological properties of the natural compounds whose anticancer activities were verified.
Contents and data retrieval
Both natural products and fractional extracts reveal a wide-spectrum distribution with respect to the biological resources and the cancer types. The NPCARE information table for a natural product includes the caner type, the scientific names of the resource organism, the compound name, PubChem ID, the names of the target gene or protein, UniProt ID of the target gene, the biological function of the target protein, COSMIC and Ensembl ID’s of the target gene, the pattern for the target gene regulation, and the cell line used for measuring the anticancer activity. The same is true of a total of 2566 extract mixtures. For each entry of NPCARE, also hyperlinked is the original scientific paper or the open resource at which the anticancer activity was reported. Users can download the entire database file by simply clicking “NPCARE CSV Download” tab in the “Useful Links” menu at NPCARE website.
Judging from the good physicochemical properties, NPCARE molecules are expected to enrich the chemical library from which a good lead compound for anticancer medicine can be identified with virtual screening. Because the natural products account for a large portion of the approved drugs , they have often served as the structural core to optimize the pharmacological activity within a series of similar compounds. Future updates of NPCARE will be focused on the increase in the number of natural products and simultaneously on the addition of the force field parameters for each natural product to facilitate the virtual screening of the potential inhibitors of various target proteins.
The result table lists not only the natural products but also the fractional extracts. The potential components of each fractional extract are displayed by clicking on ‘Get Genus Compounds List’ or ‘Get Species Compounds List’ tabs after selecting the genus and/or species names of the resource organism. All or some of the ingredients in the extract mixture may be responsible for the anticancer activity in the additive or synergistic fashions. Because the extract mixtures usually contain a number of the unknown secondary metabolites, they may offer a good opportunity to identify the novel candidate for anticancer medicine as exemplified in the discovery of chlorofusin by screening the microbial extracts to find the inhibitors of the p53–MDM2 interaction . The unique structural scaffolds of natural products can make it possible to construct a chemical library that retains the highly relevant three-dimensional aspects in cyclization and chirality. These structural peculiarities have the advantage of offering the selectivity in binding to the biomolecular target and thereby reducing the potential side effects.
Most drugs of natural origin in the clinical market stem from the plants with approximately 60% of them being clustered into only 10 taxonomic families . However, the number of plant families is extended to 197 (743 types of genus) in NPCARE, which would be beneficial to users who are seeking the new candidates for the natural anticancer medicine. Furthermore, the contents of NPCARE are augmented with the natural products and the fractional extracts isolated from the non-traditional biological resources including 164, 120, and 48 species of marine organisms, fungi, and bacteria, respectively. The inclusion of such non-traditional resources seems to be necessary because they proved to contain a variety of natural products that developed into a new anticancer medicine [20, 21]. Judging from the enrichment of the natural products and the fractional extracts isolated from a variety of plants and non-traditional biological resources, NPCARE is anticipated to serve as a useful platform for the discovery of the new natural anticancer medicines.
The construction of NPCARE database aims to promote the development of anticancer medicines from the natural resources. Each natural product entry seems to serve as a molecular scaffold using which the anticancer activity can be optimized by quantitative structure–activity relationship analysis. Users would also be able to identify the new starting points for the development of natural anticancer medicine by exploring the potential components of the fractional extracts with anticancer activity. Besides the augmentation of the traditional plant resources, NPCARE is further enriched with the natural products and the fractional extracts isolated from a variety of non-traditional biological resources. As a consequence, NPCARE contains 6578 natural compounds and 2566 fractional extracts isolated from 1952 biological resources including plants, marine organisms, fungi, and bacteria whose anticancer activities have been validated with 1107 cell lines for 34 cancer types. It is also allowed for users to construct a chemical library of the natural products specific for a cancer type as well as for a target gene or protein. Judging from the considerable amount of entries with respect to diverse resource organisms, NPCARE is anticipated to serve as a comprehensive computational platform for the discovery of new anticancer medicines.
natural products and fractional extracts for cancer regulation
Food and Drug Administration
absorption, distribution, metabolism, excretion, and toxicity
international classification of disease
American type culture collection
National Center for Biotechnology Information
HUGO gene nomenclature committee
catalogue of somatic mutations in cancer
calculated partition coefficient
hydrogen bond acceptor
hydrogen bond donor
HC and HP designed the database and wrote the paper. HC and TH constructed the website. HJP, YK, JC, YJL, BHG, YSK, GC, YC, SL, and DR participated in collecting and processing the data. All authors read and agreed to the final manuscript.
Authors thank Hanvit Dental Medical Foundation for many helpful discussions.
All the authors declare that they have no competing interests.
Availability and requirements
NPCARE is publicly accessible without charge at http://silver.sejong.ac.kr/npcare.
The present study was fully supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1D1A1B01014187). This made it possible to design the study and collection, analysis, and interpretation of data and to prepare the manuscript.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Collins I, Workman P (2006) New approaches to molecular cancer therapeutics. Nat Chem Biol 12:689–700View ArticleGoogle Scholar
- Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335View ArticleGoogle Scholar
- Hert J, Irwin JJ, Laggner C, Keiser MJ, Shoichet BK (2009) Quantifying biogenic bias in screening libraries. Nat Chem Biol 5:479–483View ArticleGoogle Scholar
- Schenone M, Dancik V, Wagner BK, Clemons PA (2013) Target identification and mechanism of action in chemical biology and drug discovery. Nat Chem Biol 9:232–240View ArticleGoogle Scholar
- Dunkel M, Fullbeck M, Neumann S, Preissner R (2006) SuperNatural: a searchable database of available natural compounds. Nucleic Acids Res 34:D678–D683View ArticleGoogle Scholar
- Ahmed J, Meinel T, Dunkel M, Murgueitio MS, Adams R, Blasse C, Eckert A, Preissner S, Preissner R (2011) CancerResource: a comprehensive database of cancer-relevant proteins and compound interactions supported by experimental knowledge. Nucleic Acids Res 39:D960–D967View ArticleGoogle Scholar
- Mangal M, Sagar P, Singh H, Raghava GPS, Agarwal SM (2013) NPACT: naturally occurring plant-based anti-cancer compound-activity-target database. Nucleic Acids Res 41:D1124–D1129View ArticleGoogle Scholar
- Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, Xu X, Li Y, Wang Y, Yang L (2014) TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 6:13View ArticleGoogle Scholar
- Tao W, Li B, Gao S, Bai Y, Shar PA, Zhang W, Guo Z, Sun K, Fu Y, Huang C, Zheng C, Mu J, Pei T, Wang Y, Li Y, Wang Y (2015) CancerHSP: anticancer herbs database of systems pharmacology. Sci Rep 5:11481View ArticleGoogle Scholar
- Xue R, Fang Z, Zhang M, Yi Z, Wen C, Shi T (2013) TCMID: traditional Chinese medicine integrative database for herb molecular mechanism analysis. Nucleic Acids Res 41:D1089–D1095View ArticleGoogle Scholar
- Pathania S, Ramakrishnan SM, Bagler G (2015) Phytochemica: a platform to explore phytochemicals of medicinal plants. Database 2015:bav075
- Zhao L, Nicholson JK, Lu A, Wang Z, Tang H, Holmes E, Shen J, Zhang X, Li JV, Lindon JC (2012) Targeting the human genome-microbiome axis for drug discovery: inspirations from global systems biology and traditional Chinese medicine. J Proteome Res 11:3509–3519View ArticleGoogle Scholar
- Barlow D, Buriani A, Ehrman T, Bosisio E, Eberini I, Hylands P (2012) In silico studies in Chinese herbal medicines’ research: evaluation of in silico methodologies and phytochemical data sources, and a review of research to date. J Ethnopharmacol 140:526–534View ArticleGoogle Scholar
- May BH, Lu C, Xue CC (2012) Collections of traditional Chinese medical literature as resources for systematic searches. J Altern Complement Med 18:1101–1107View ArticleGoogle Scholar
- Choi H, Kang H, Park H (2011) MetLigDB: a web-based database for the identification of chemical groups to design metalloprotein inhibitors. J Appl Cryst 44:878–881View ArticleGoogle Scholar
- Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25View ArticleGoogle Scholar
- Quinn RJ, Carroll AR, Pham NB, Baron P, Palframan ME, Suraweera L, Pierens GK, Muresan S (2008) Developing a drug-like natural product library. J Nat Prod 71:464–468View ArticleGoogle Scholar
- Duncan SJ, Grüschow S, Williams DH, McNicholas C, Purewal R, Hajek M, Gerlitz M, Martin S, Wrigley SK, Moore M (2001) Isolation and structure elucidation of Chlorofusin, a novel p53-MDM2 antagonist from a Fusarium sp. J Am Chem Soc 123:554–560View ArticleGoogle Scholar
- Sharma V, Sarkar IN (2013) Leveraging biodiversity knowledge for potential phyto-therapeutic applications. J Am Med Inform Assoc 20:668–679View ArticleGoogle Scholar
- McBride A, Butler SK (2012) Eribulin mesylate: a novel halichondrin B analogue for the treatment of metastatic breast cancer. Am J Health Syst Pharm 69:745–755View ArticleGoogle Scholar
- Yu MJ, Zheng W, Seletsky BM (2013) From micrograms to grams: scale-up synthesis of eribulin mesylate. Nat Prod Rep 30:1158–1164View ArticleGoogle Scholar