Investigate linking MoA/Roles to Activities to Activity objects

[stuppie]

These 4 items exist in Wikidata but aren't connected in any way. They would be useful to be able to answer questions like: What drugs could I use to inhibit the action of ABL2?

protein kinase inhibitor activity (GO term) Protein kinase inhibitors (mesh, chebi, ndfrt, atc. drugs that exhibit pki activity) protein kinases (e.c. number (EC 2.7.11.1), not really linked to anything but the wikipedia article) Protein kinase-like domain superfamily (protein family. Linked to more specific protein families, annotated to specific proteins. Example cdk2 'part of' pk superfamily)

From GO: protein kinase inhibitor activity (GO:0004860) | directly_negatively_regulates | protein tyrosine kinase activity (GO:0004713) protein tyrosine kinase activity (GO:0004713) | has mapping | EC 2.7.10

From Chebi: EC 2.7.10.* (protein-tyrosine kinase) inhibitor (CHEBI:76817) | is a | protein kinase inhibitor (CHEBI:37699)

From MeSH: This isn't totally structured, but we could make it work.. Protein Kinase Inhibitors (D047428) | note | Agents that inhibit PROTEIN KINASES Protein Kinases | Registry Number | EC 2.7.-

From Uniprot: we can get specific protein's EC numbers P42684 (ABL2_HUMAN) | ec number | 2.7.10.2 or annotated go terms: P42684 (ABL2_HUMAN) | GO - Molecular function | protein tyrosine kinase activity (GO:0004713)

From Interpro: Protein kinase-like domain superfamily | ec number | 2.7

[stuppie]

A more straightforward example:

From MeSH:

proquazone -> has role -> Cyclooxygenase Inhibitors (Q26697606) Cyclooxygenase Inhibitors (Q26697606) -> subclass of -> non-steroidal anti-inflammatory drug Cyclooxygenase Inhibitors (Q26697606) -> subclass of -> enzyme inhibitor

Ideally, we'd want to connect "Cyclooxygenase Inhibitors" semantically with the "Cyclooxygenase" protein class, and the action "inhibits"

We can get the E.C. number and action from Chebi (note: technically, license is incompatible). I've manually linked many MeSH and Chebi roles, so we can get from the mesh to chebi. For example: EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor. The EC number is in the name in a systematic way, and this is a subclass of enzyme inhibitor (CHEBI:23924)

From the EC number, we can get proteins with that EC number. So would be able to infer, for example, from the statement that

'proquazone' is a 'Cyclooxygenase Inhibitor'

that

'proquazone' inhibits the action of COX-1 and COX-2

The missing links to be able to do this:

1. Linking Enzyme Modulators to the enzyme class and action (i.e. agonist, antagonist, etc.)
2. Linking specific proteins to their class

[stuppie]

Not all MoAs / Roles will be able to be semantically annotated like this. Examples:

CHEBI:38633 - sodium channel blocker is not semantically linked to "sodium channels" in any way

CHEBI:66902 - CFTR potentiator ideally would be linked to the protein CFTR. Has a wikipedia link to the page for CFTR

CHEBI:85384 - GABA reuptake inhibitor

Example of Roles that are not related to specific enzymatic or receptor activities:

anti-inflammatory agent (Q581996) -> inhibits -> inflammatory response (GO:0006954) Is this useful? Does that mean we can infer that all drugs that are anti-inflammatory agents inhibit all proteins with the biological process "inflammatory response" ? I don't think so. This seems overly broad.

[stuppie]

Linking Enzyme Modulators to the enzyme action

Terms that describe drug action (in relation to a receptor) (source: http://www.iuphar-db.org/GPCR/termsAndSymbols.pdf)

• Agonist (https://www.wikidata.org/wiki/Property:P3772)
  • Full agonist
  • Inverse agonist
  • Partial agonist
• Antagonist (https://www.wikidata.org/wiki/Property:P3773)
  • Noncompetitive antagonism (blocking/blocker) (https://www.wikidata.org/wiki/Property:P3774)
  • Competitive antagonism
• Allosteric (allotopic) modulator
  • Positive (https://www.wikidata.org/wiki/Property:P3778)
  • Negative (https://www.wikidata.org/wiki/Property:P3779)

Terms that describe drug action (in relation to an enzyme)

• Inhibitor (https://www.wikidata.org/wiki/Property:P3776)
• Activator (https://www.wikidata.org/wiki/Property:P3771)
• Reactivator

Others

• antisense inhibitor of (https://www.wikidata.org/wiki/Property:P3777)
• disrupting agent for (https://www.wikidata.org/wiki/Property:P3775)

[stuppie]

Linking Enzyme Modulators to the enzyme

Not sure the best way to do this.... Here is a suggestion:

I think there are GO terms for each role (query by EC number). The drug MoA could be linked through the GO activity it modulates. You could then query for proteins that are annotated with that GO activity.

Example:

cyclooxygenase inhibitors (the class of drugs) -> inhibitor of -> prostaglandin-endoperoxide synthase activity (the activity, defined by GO) COX-1 protein (Prostaglandin-endoperoxide synthase 1) -> molecular function -> prostaglandin-endoperoxide synthase activity

Sodium channel blocker -> blocker of (P3774) -> sodium channel activity Or??? Sodium channel blocker -> has role -> sodium channel inhibitor activity