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

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.

The target landscape of N4-hydroxycytidine based on its chemical neighborhood

“…Beyond the three drugs discussed above, there are two structurally close molecules that deserve consideration (Figure 3). One of them is cytidine, the endogenous substrate of several nucleoside transporters [24], such as the sodium/nucleoside cotransporter 1 (SLC28A1), the solute carrier family 28 member 3 (SLC28A3), and the equilibrative nucleoside transporter 1 (SLC29A1). And the other one is N6-hydroxyadenosine (NHA), a known active molecule against tyrosyl-DNA phosphodiesterase 1 (TDP1) [25] and also shown to act as a potent antiviral [26].…”

“…Beyond the three nucleoside transporters mentioned above that interact with cytidine, uridine binds to the sodium-dependent nucleobase transporter (SLC23A4), the equilibrative nucleoside transporter 2 (SLC29A2), and the equilibrative nucleoside transporter 3 (SLC29A3) [24]. In addition, uridine is also the result of the catalytic activity of cytidine deaminase (CDA) on its endogenous metabolite, cytidine.…”

“…In turn, uridine can also be transformed into uridine triphosphate that will then bind to several pyrimidinergic receptors, such as P2Y2 and P2Y4 [24].…”

“…Finally, the structural similarity of adenosine to NHC will translate into its triphosphate metabolite (ATP) being also in the chemical neighborhood of NHCTP, with all derived consequences in biology. ATP is the endogenous ligands for purinergic (P2X) and pyrimidinergic (P2Y) receptors, it is the substrate or product of numerous enzyme catalytic reactions (such as mevalonate kinase, sphingosine kinases or acetyl-CoA carboxylases) and binds also to several ion channels (such as the transient receptor potential TRPM4 or the inositol and ryanodine receptor channels) [24]. Consequently, all these targets are also likely to interact with NHCTP and they should be added to the list of targets associated with NHC.…”

Opening up Connectivity Between Documents, Structures and Bioactivity

“…We can describe the connectivity between documents, structures and bioactivity as conceptual triage routinely performed by readers of medicinal chemistry or pharmacology papers [5]. Typically, we peruse a document "D" that describes a bioactivity "A" with a quantitative result "R" (e.g.…”