Databases of natural products

In addition to this historical success in drug discovery, natural products are likely to continue as sources of new commercially viable drug leads. The chemical novelty associated with natural products is higher than that of any other source 40% of the chemical scaffolds in a published database of natural products (Dictionary of Natural Chemistry). This is particularly important when searching for lead molecules against newly discovered targets. Despite commonly held assumptions, natural products can be a more economical source of chemical diversity than the synthesis of equivalent diverse chemicals. 

Of course, there are intrinsic disadvantages with this approach. For example, the rediscovery of known compounds is common, so it is important to have a suitable "de-replication" step early in the process. Active extracts are therefore compared by HPLC-MS with our database of natural products, and those containing compounds already known to us are discarded. Another disadvantage is that substantial time and effort are invested before the natural product is finally isolated and its structure ruid bioactivity are determined, and the result can often be disappointing. However, the expectation is that the discovery of a small proportion of exciting natural products will make the whole exercise worthwhile. 

Pharmacophore 9676 compounds from the DIOS database of natural products found in ancient herbal medicines described in De materia medica and 10,216 compounds from the Chinese herbal medicine (CHM) database Partial 4 3 [98]... 

The DNP (Chapman HaU/CRC Dictionary of Natural Products) is a comprehensive literature database of around 170 000 isolated natural products from various sources and provides names, chemical structures, CAS registry numbers, extensive source data, uses and applications. 

The Dictionary of Natural Products database is available from Chapman HaU/CRC Press at http //www.chemnetbase.com... 

For this task, easily accessible properties of mixtures or pure metabolites are compared with literature data. This may be the biological activity spectrum against a variety of test organisms. Widely used also is the comparison of UV [90] or MS data and HPLC retention times with appropriate reference data collections, a method which needs only minimal amounts and affords reliable results. Finally, there are databases where substructures, NMR or UV data and a variety of other molecular descriptors can be searched using computers [91]. The most comprehensive data collection of natural compounds is the Dictionary of Natural Products (DNP) [92], which compiles metabolites from all natural sources, also from plants. More appropriate for dereplication of microbial products, however, is our own data collection (AntiBase [93]) that allows rapid identification using combined structural features and spectroscopic data, tools that are not available in the DNP. 

Bukingham J, Thompson S (1997) Dictionary of natural products and other information somces for natmal products scientists. In Phytochemical diversity - a somce of new industrial products. Royal Society of Chemistry, London, pp 53-67 (2001) Dictionary of Natmal Products on CD-ROM, Chapman and HaU/CRC Press Laatsch H (1994 and annual updates) AntiBase, A database for rapid structmal determination of microbial natmal products. Chemical Concepts, Weinheim, Germany Breheret S, Talou T, Rapior S, Bessiere JM (1997) J Agric Food Chem 45 831 Schulz S (2001) private commimication, Braunschweig, Germany Burkholder PR, Pfister RM, Leitz FH (1966) Appl Microbiol 14 649 Reid RT, Live DH, Faulkner DJ, Butler A (1993) Nature 366 455... 

In view of the abundance of natural products known to us, a collection such as this one must of course restrict itself to a few representatives from important classes of substances. At any rate, for a comprehensive collection of as much information as possible on as many natural products as possible, databases with their search possibilities are more suitable. However, one must bear in mind that data is often missing for products which were described some time ago this occurs, for example, because only the more recent publications have been included in databases. 

Use of an integrated system incorporating CCC separation, PDA detector, and LC-MS proved to be a valuable tool in the rapid identification of known compounds from microbial extracts.6 This collection of analytical data has enabled us to make exploratory use of advanced data analysis methods to enhance the identification process. For example, from the UV absorbance maxima and molecular weight for the active compound(s) present in a fraction, a list of potential structural matches from a natural products database (e.g., Berdy Bioactive Natural Products Database, Dictionary of Natural Products by Chapman and Hall, etc.) can be generated. Subsequently, the identity of metabolite(s) was ascertained by acquiring a proton nuclear magnetic resonance ( H-NMR) spectrum. 

Bradshaw et al. have disclosed a rapid and facile method for the dereplication of a purified natural product library [58]. The method integrates the molecular weight from low resolution MS data with the exact count of the number of methyl, methylene and methine groups obtained from ]H-13C NMR correlation data. Those structure properties were converted into a searchable text file that could be downloaded into a customized software program with chemical structure information in a specific format - SMILES. In the program, more than 120,000 unique structures were derived from commercial databases, such as Dictionary of Natural Products and Beilstein. 

Natural product structures were obtained from the Dictionary of Natural Products (DNP, Chapman Hall, n 78 318) and the biologically active Natural Products Database (BNPD, compiled by Berdy of Szenzor Management Consulting Company, Budapest, n=29 432). These two databases cover most of the natural products and their derivatives. 

There are numerous natural product databases that are used in dereplication such as Chemical Abstracts Service (CAS), Berdy s Bioactive Natural Products Database, Dictionary of Natural Products, MarinLit23 and AntiBase.24 Integration of structure-based and chemical shift searches, such as NAPROC-13,25 make these databases even more valuable. AntiMarin is a result of a recent merger between AntiBase and MarinLit 26 MarinLit and AntiMarin are the first commercially available databases that contain structural information (functional groups) as searchable fields.27... 

Recent advances in chemoinformatics have greatly enhanced the utility of these resources and many are now accessible via the Internet.28 CHEMnet-BASE (www.chemnetbase.com) provides online access to a variety of databases including the Dictionary of Natural Products and the Dictionary of Marine Natural Products, although full access through CHEMnetBASE requires a subscription. The Chemical Structure Lookup Service (http //cactus.nci.-nih.gov/lookup) is an open access database and incorporates information from more than 80 databases on over 27 million structures. PubChem (http //pub-chem.ncbi.nlm.nih.gov/) is another open access database that also links bioassay data to each structure. Measures such as the US National Institutes of Health (NIH) Public Access Policy Mandate should increase the amount of openly accessible information available on the Internet and facilitate dissemination of information. 

ChemCore module to three-dimensionalize 2D structures, interfaces to reformat MACCS, SMILES, or DARC-2D databases, ChemDBS-1 module to build 3D databases, and ChemDBS-3D module to search 3D databases. Database searching accounts for conformational flexibility while storing only one conformation. Chapman 8c Hall s 3D Dictionary of Drugs (12,000 medicinally interesting compounds), 3D Dictionary of Natural Products (50,000 antibiotics, alkaloids, and terpenoids), and 3D Dictionary of Fine Chemicals (105,000 organics). 

The best information source on the names of natural products is the Dictionary of Natural Products (DNP), which is part of the Chapman Hall/CRC chemical database (see Section 1.2.1). DNP does not give CAS names where these are lengthy, but it does have extensive coverage of CAS numbers, from which the current CAS name can be readily obtained if needed. 

There are literally thousands of published scientific papers from around the globe describing the antimicrobial activities of natural products [14-17], A search of the PubMed database (data from 1975 to 2005, available on the Internet) produced approximately 1360 reports in the scientific and medical literature that described the antimicrobial activities of various plant species and their chemical constituents. Furthermore, a search of the Napralert database, the world s largest natural products database housed within the University of Illinois at... 

J. Buckingham, Exc. Ed., Dictionary of Natural Products, Chapman Hall Chemical Database, Vol.7, N.Y. 1994. 

In the pharmaceutical industry, the techniques are being used to examine off-target effects particularly for the early identification of toxicity. MOA can be studied through metabolomics and can also be used as a quality control tool for complex mixtures such as foods or herbal medicines. Similarly, the tools and expertise of natural products chemists are essential in metabolomics, particularly in biomarker discovery (see also Volume 9). Biomarker discovery via untargeted metabolomics can lead to metabolite signatures (nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), etc.) that are not present in current metabolomics databases. This is particularly true for plant secondary metabolism studies and nonmammalian metabolites. Structure elucidation then becomes critical to understanding the metabolomics results and for biomarker development. 

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