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Review
. 2018 Jul 31;3(7):8408-8420.
doi: 10.1021/acsomega.8b00884.

Challenges of Connecting Chemistry to Pharmacology: Perspectives From Curating the IUPHAR/BPS Guide to PHARMACOLOGY

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Free PMC article
Review

Challenges of Connecting Chemistry to Pharmacology: Perspectives From Curating the IUPHAR/BPS Guide to PHARMACOLOGY

Christopher Southan et al. ACS Omega. .
Free PMC article

Abstract

Connecting chemistry to pharmacology has been an objective of Guide to PHARMACOLOGY (GtoPdb) and its precursor the International Union of Basic and Clinical Pharmacology Database (IUPHAR-DB) since 2003. This has been achieved by populating our database with expert-curated relationships between documents, assays, quantitative results, chemical structures, their locations within the documents, and the protein targets in the assays (D-A-R-C-P). A wide range of challenges associated with this are described in this perspective, using illustrative examples from GtoPdb entries. Our selection process begins with judgments of pharmacological relevance and scientific quality. Even though we have a stringent focus for our small-data extraction, we note that assessing the quality of papers has become more difficult over the last 15 years. We discuss ambiguity issues with the resolution of authors' descriptions of A-R-C-P entities to standardized identifiers. We also describe developments that have made this somewhat easier over the same period both in the publication ecosystem and recent enhancements of our internal processes. This perspective concludes with a look at challenges for the future, including the wider capture of mechanistic nuances and possible impacts of text mining on automated entity extraction.

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Example of a D-A-R-C-P relationship chain. Taken from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9001.
Figure 2
Figure 2
Relationships within the Entrez system available as links from the right-hand facets of a PubMed entry. “Similar articles” is essentially a heuristic clustering of “aboutness”, while “cited by” provides forward connectivity within the same knowledge domain. “Related information” links to NCBI database cross-references including PubChem Substance (SID), Compound (CID), and BioAssay, MeSH keyword matches, and protein structures in the Protein Data Bank (PDB). In this case, the three “PubChem substance” links have entered the system via the PubChem submissions from GtoPdb (see section below on PubChem links). The “MeSH keyword” look-up brings back three CIDs for BIA 10-2474, PF-04457845, and the less relevant urea (n.b. MeSH annotators did not select the metabolite BIA 10-2639 as a keyword but could do if this becomes a main theme of a future paper).
Figure 3
Figure 3
GtoPdb entry for FAAH (GtoPdb Target ID (TID) 1440) with inhibitors mapped to it from the database release 2018.1. The record for PF-04457845 is expanded to show the activity and references. Descriptions of the icons and rows are given in the GtoPdb Help documentation and FAQs.
Figure 4
Figure 4
Distribution of papers curated for ligand interactions in GtoPdb (release 2018.1). Numbers of papers are shown on the horizontal axis. The vertical axis of journal titles shows the top-20 journals from a total of 920.
Figure 5
Figure 5
Six principal types of chemical representation or routes of interconversion encountered and/or used during the curation of structures from papers. Most cheminformatic tool-kits can execute the interconversions indicated by the arrows and major chemistry databases will also precompute links between them. However, the round-tripping may not be perfect. Note also that the InChIKey cannot be converted to a structure but has key utilities, including as a look-up string in Google.
Figure 6
Figure 6
Supplementary data from ref (39) with verubecestat as “compound 3”.
Figure 7
Figure 7
Image for alvelestat from the INN proposal document. This included the IUPAC name: N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide.
Figure 8
Figure 8
CIDs retrieved from PubChem with the term “alvelestat”. The SID counts for each of these in descending order are 3, 5, 45, and 7.

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