To confound the issue, some energy products (eg,5-Hour Energy,Monster Energy,Rockstar) are mar-keted as dietary supplements, while others (eg,Red-Bull) are marketed as conventional foods.4,5Althoughthe FDA regulates both dietary supplements and con-ventional foods under the Federal Food, Drug, andCosmetic Act (FFDCA), the requirements for theseproducts are different, including the process for mar-keting and reporting of adverse events post marketing.

PubChem is an archive.  When a record is updated, it is versioned and the original record is retained and accessible.  These dates are more prominent and now includes a modification date table for easy access.  For example, the Substance Record page for SID 12345 has multiple versions:

substance is a contributed chemical substance sample description from a particular PubChem data provider.  A compound is a normalized chemical structure representation found in one or more contributed substance

Data is provided by hundreds of contributors (http://pubchem.ncbi.nlm.nih.gov/sources/), including publishers, researchers, chemical vendors, pharmaceutical companies, and a number of important chemical biology resources.  Each of these data sources contributes a description of chemical substance samples for which they have information.

A substance is a contributed chemical substance sample description from a particular PubChem data provider

The distinction is important as PubChem is organized in three separate databases: Compound, Substance, and BioAssay. 

(22)      ToxNet (http://toxnet.nlm.nih.gov/) (Accessed on 2/19/2017).

Therefore, it is very common that database groups exchange their information with each other. 

Although the data provenance information is critical in the reliability of a data source (and its data), this information is not easy to manage. 

In turn, users should always pay attention to the data provenance issue when using a database.

TOXNET (http://toxnet.nlm.nih.gov/)22-25, maintained by the National Library of Medicine (NLM) at NIH, is a group of databases covering toxicology, hazardous chemicals, toxic releases, environmental and occupational health, risk assessment.  Currently, 16 databases are integrated into the TOXNET system, and users can search all these databases either at once or individually.  While all the 16 databases provide valuable information, three of them may be worth mentioning in the context of this course.

The error propagation issue is a serious, but very common, problem.39,40  Therefore, when using information in these databases, one should keep in mind various data accuracy and quality issues prevalent in these databases.

As of February 2017, PubChem contains more than 235 million depositor-provided substances, 94 million unique chemical structures, and one million biological assays, which cover about 10 thousand protein target sequences.

2.5. NIST Webbook: thermodynamic and spectroscopic data of chemicals

It is very common that a primary database curates its data with information drawn from secondary databases. 

TOXNET (http://toxnet.nlm.nih.gov/)22-25, maintained by the National Library of Medicine (NLM) at NIH, is a group of databases covering toxicology, hazardous chemicals, toxic releases, environmental and occupational health, risk assessment. 

As of February 2017, PubChem’s data are from more than 500 organizations, including government agencies, university labs, pharmaceutical companies, substance vendors, and other databases

Getting the most out of PubChem for virtual screening

The term “data provenance” refers to a record trail that describes the origin or source of a piece of data and the process by which it entered in a database.1 

(d) Explain the reason why the “legacy” designation was introduced in PubChem in two or three sentences.

Some records in PubChem are “non-live”, meaning that they are “not searchable”, although they do exist in the database.  This exercise is designed to help students better understand what non-live records are.

Therefore, databases need to document the provenance of the data and devise a way to notify users of that information.  In turn, users should always pay attention to the data provenance issue when using a database.  

ChEMBL:

PubChem organizes its data into three inter-linked databases: Substance, Compound, and BioAssay (See Table 1), which can be searched from either the PubChem home page (https://pubchem.ncbi.nlm.nih.gov) or the web page of one of the three PubChem databases.   Table 1. Three inter-linked databases in PubChem. Database URL Identifier Substance https://www.ncbi.nlm.nih.gov/pcsubstance SID Compound https://www.ncbi.nlm.nih.gov/pccompound CID BioAssay https://www.ncbi.nlm.nih.gov/pcassay AID   Individual data contributors deposit information on chemical substances to the Substance database (https://www.ncbi.nlm.nih.gov/pcsubstance).  Different data contributors may provide information on the same molecule, hence the same chemical structure may appear multiple times in the Substance database.  To provide a non-redundant view, chemical structures in the Substance database are normalized through a process called “standardization” and the unique chemical structures are identified and stored in the Compound database (https://www.ncbi.nlm.nih.gov/pccompound).  The difference between the Substance and Compound databases is explained in more detail in this blog post.

1.2. Primary databases vs. secondary databases

Table 1. Three inter-linked databases in PubChem. Database URL Identifier Substance https://www.ncbi.nlm.nih.gov/pcsubstance SID Compound https://www.ncbi.nlm.nih.gov/pccompound CID BioAssay https://www.ncbi.nlm.nih.gov/pcassay AID  

ChemIDPlus26,27 is a dictionary of over 400,000 chemical records (names, synonyms, and structures) and provides access to the structure and nomenclature files used for the identification of chemical substances in the TOXNET system and other NLM databases.  The Hazardous Substances Data Bank (HSDB)28,29 focuses on the toxicology of potentially hazardous chemicals, providing information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. All HSDB data are referenced and derived from a core set of books, government documents, technical reports and selected primary journal literature. Importantly, HSDB is peer-reviewed by the Scientific Review Panel (SRP), a committee of experts in the major subject areas within the data bank's scope. The Comparative Toxicogenomics Database (CTD)30,31  contains manually curated data describing interactions of chemicals with genes/proteins and diseases.  This database provides insight into the molecular mechanisms underlying variable susceptibility for environmentally influenced diseases

All information in the Substance database is submitted by individual data depositors.  However, the Compound database does contain information that are not submitted by data depositors,

1.2. Primary databases vs. secondary databases     Databases are often categorized into primary and secondary databases.  Primary databases contain experimentally-derived data that are directly submitted by researchers (also called “primary data”).  In essence, these databases serve as archives that keep original data.  Therefore, they are also known as archival databases. Secondary databases contain secondary data, which are derived from analyzing and interpreting primary data.  These databases often provide value-added information related to the primary data, by using information from other databases and scientific literature.  Essentially, secondary databases serve as reference libraries for the scientific community, providing highly curated reviews about primary data.  For this reason, they are also known as curated databases, or knowledgebase.

  PubChem organizes its data into three inter-linked databases: Substance, Compound, and BioAssay (See Table 1), which can be searched from either the PubChem home page (https://pubchem.ncbi.nlm.nih.gov) or the web page of one of the three PubChem databases.   Table 1. Three inter-linked databases in PubChem. Database URL Identifier Substance https://www.ncbi.nlm.nih.gov/pcsubstance SID Compound https://www.ncbi.nlm.nih.gov/pccompound CID BioAssay https://www.ncbi.nlm.nih.gov/pcassay AID   Individual data contributors deposit information on chemical substances to the Substance database (https://www.ncbi.nlm.nih.gov/pcsubstance).  Different data contributors may provide information on the same molecule, hence the same chemical structure may appear multiple times in the Substance database.  To provide a non-redundant view, chemical structures in the Substance database are normalized through a process called “standardization” and the unique chemical structures are identified and stored in the Compound database (https://www.ncbi.nlm.nih.gov/pccompound).  The difference between the Substance and Compound databases is explained in more detail in this blog post.

1.2. Primary databases vs. secondary databases     Databases are often categorized into primary and secondary databases.  Primary databases contain experimentally-derived data that are directly submitted by researchers (also called “primary data”).  In essence, these databases serve as archives that keep original data.  Therefore, they are also known as archival databases. Secondary databases contain secondary data, which are derived from analyzing and interpreting primary data.  These databases often provide value-added information related to the primary data, by using information from other databases and scientific literature.  Essentially, secondary databases serve as reference libraries for the scientific community, providing highly curated reviews about primary data.  For this reason, they are also known as curated databases, or knowledgebase.

ChEMBL: literature-extracted biological activity information         ChEMBL (https://www.ebi.ac.uk/chembl/)8,9 is a large bioactivity database, developed and maintained by the European Bioinformatics Institute (EBI), which is part of the European Molecular Biology Laboratory (EMBL).  The core activity data in ChEMBL are “manually” extracted from the full text of peer-reviewed scientific publications in select chemistry journals, such as Journal of Medicinal Chemistry, Bioorganic Medicinal Chemistry Letters, and Journal of Natural products.  From each publication, details of the compounds tested, the assays performed and any target information for these assays are abstracted.  ChEMBL also integrates screening results and bioactivity data from other public databases (such as PubChem BioAssay) and information on approved drugs from the U.S. FDA Orange Book10 and the NLM’s DailyMed

Public Chemical Databases         These days many public online databases provide chemical information free of charge and the databases mentioned in this module are only a few examples of them.  Note that these databases vary in size and scope.   2.1. PubChem: chemical information repository at the U.S. NIH         PubChem (https://pubchem.ncbi.nlm.nih.gov)2-4 is a public repository of information on small molecules and their biological activities, developed and maintained by the National Library of Medicine (NLM), an institute within the U.S. National Institutes of Health (NIH).  Since its launch in 2004 as a component of the NIH’s Molecular Libraries Roadmap Initiatives, it has been rapidly growing, and now serves as a key chemical information resource for researchers in many biomedical science areas, including cheminformatics, chemical biology, and medicinal chemistry.  Detailed information on PubChem can be found in these three papers:

The Protein Data Bank (PDB) is an archive of the experimentally determined 3-D structures of large biological molecules such as proteins and nucleic acids.

Unique Ingredient Identifiers (UNIIs) and pharmacological classifications were added from the U.S. Food and Drug Administration (FDA).

For example, to access the old version of the Compound Summary page for Aspirin:

PubChem is organized as three interconnected databases: Substance, Compound, and BioAssay

The BioAssay database (https://www.ncbi.nlm.nih.gov/pcassay)

Alternatively, PubChemRDF data can also be loaded into RDF-aware graph databases such as Neo4j, and the graph traversal algorithms can be used to query the PubChem knowledge graphs.

In 2-D similarity search, the similarity between chemical structures is quantified using the Tanimoto equation (22–24) in conjunction with the PubChem substructure fingerprint

PubChem standardization process in which unique chemical structures are extracted from the Substance database and stored in the Compound database.

178 deg C (sublimes)

Sublimation is one way to purify the sample, because caffeine has the ability to pass directly from the solid to vapor and reverse to form a solid all without undergoing the liquid phase. Caffeine has the ability to undergo sublimation under different conditions than the impurities, and can thus be isolated

PubChem implements both manual and automated processes

If a data contributor is designated as “legacy”, all records deposited by the contributor are also designated as “legacy”. 

Therefore, some records in PubChem can persist with outdated (or incorrect) data.  To help identify such cases, we are introducing a “legacy” indication for contributors and their records.  Please note that this does not mean that data identified as “legacy” is without value.

Therefore, some records in PubChem can persist with outdated (or incorrect) data.  To help identify such cases, we are introducing a “legacy” indication for contributors and their records.  Please note that this does not mean that data identified as “legacy” is without value.  Quite to the contrary, some legacy collections successfully collected valuable scientific data for the research community, and are simply no longer updating the information.

This “legacy” designation applies to project/contributors that appear to no longer be active, as well as to their individual records.  This designation will help PubChem users quickly identify records that may have out-of-date information and/or hyperlinks.

Lipinski’sruleof5[50].Among them, 10.3 million (12% of the total) are fragment-like ones, which satisfy Congreve’sruleof3[51].

Therefore, 3-D neighboring may offer comple-mentary views on structural similarity between molecules withsimilar biological activities.

Forexample, ChEMBL [49] manually extracts bioactivity datafrom peer-reviewed papers published in journals in themedicinal chemistry and natural product domains.

he table of contents on a PubChem summary page lists the categories of information that are available for the particular substance or compound. A PubChem Substance summary page is based on the data submitted by an individual depositor. A PubChem Compound summary page, on the other hand, displays data organized by NCBI automated data processing, serving as a hub of information for each unique chemical structure. PubChem Compound summary pages therefore tend to list more topics in their table of contents.

The PubChem Substance database contains substance information (often including the chemical structure) that was submitted to NCBI by individual submitters (depositors). The PubChem Compound records comprise a non-redundant set of standardized and validated chemical structures. A PubChem Compound record may link to more than one PubChem Substance record if different depositors supplied the same structure. Chemical names shown in PubChem Compound records are a composite derived from all linked substances, with default ranking of names by weighted frequency of use.