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Chemical Biology Curation Guidelines

This document containts an initial (and as-of-yet incomplete) set of guidelines for representing quantitative information in BEL. They do not require any special extensions to its syntax, and should be compatible with any of the available parsers/compilers.

There is currently a BEL enhancement propopsal for BEL 2.0.0+ for native support of numeric annotations that would benefit from public input, so that's highly encouraged!

Inhibitors

This example will focus on the ability for lovastatin (CHEMBL1487) to inhibit human HMG-CoA reductase (CHEMBL402, UniProt:P04035, HGNC:HMGCR, HGNC:5006).

Simple Representation

a(CHEMBL:CHEMBL1487) =| act(p(UNIPROT:P04035))

Medium-Granular Representation with BEL Default Namespace

a(CHEMBL:CHEMBL1487) =| act(p(UNIPROT:P04035), ma(cat))

Specific Representation

Using BEL 2.0, the molecular function HMGCR that lovastatin inhibits is its (hydroxymethylglutaryl-CoA reductase (NADPH) activity (GO:0004420).

a(CHEMBL:CHEMBL1487) =| act(p(UNIPROT:P04035), ma(GO:0004420))

In general, it might not be so obvious how specific of a GO term to choose. Additionally, a protein may have multiple functions. Complementary to GO is the ExPASy enzyme classification, which is also encoded in ChEBI and can be automatically added to BEL.

Assay Metadata

Taking inspiration from the ChEBML schema, several pieces of metadata can make inhibition experiments more useful:

  1. Target Type (e.g., cell line, organism, single protein, complex, etc.)
  2. Measurement Type (e.g., IC50, pIC50, EC50, pEC50, Ki)
  3. Measurement Units (e.g., pM, nM, μM, mM, M)
  4. Measurement Relation (=, >, <, >=, <=, ~)
  5. Measurement Value (floating point matching the regular expression: ^[-+]?[0-9]*\.?[0-9]+([eE][-+]?[0-9]+)?$)
  6. Assay Type (see below)
  7. Cell line, target organism, and/or species

In some cases, the measurement value may be reported as a range. In these situations, use two complementary annotations for Measurement Range Lower and Measurement Range Upper.

Assay Type (adapted from ChEMBL)

  • Binding (B) - Data measuring binding of compound to a molecular target, e.g. Ki, IC50, Kd.
  • Functional (F) - Data measuring the biological effect of a compound, e.g. %cell death in a cell line, rat weight.
  • ADMET (A) - ADME data e.g. t1/2, oral bioavailability.
  • Toxicity (T) - Data measuring toxicity of a compound, e.g., cytotoxicity.
  • Physicochemical (P) - Assays measuring physicochemical properties of the compounds in the absence of biological material e.g., chemical stability, solubility.
  • Unclassified (U) - A small proportion of assays cannot be classified into one of the above categories e.g., ratio of binding vs efficacy.

After adding this metadata, we get:

SET AssayType = "B"
SET MeasurementType = "IC50"
SET MeasurementUnits = "nM"
SET MeasurementRelation = "="
SET MeasurementValue = "0.5"

SET Species = "9606"
SET Cell = "HEPG2"

a(CHEMBL:CHEMBL1487) =| act(p(UNIPROT:P04035), ma(GO:0004420))

Provenance

Using a valid citation that points to the original source of the information is preferred to using a reference to the database from which the relation comes. Example: it's better to use PMID:2153213 in these examples referring to its original publication rather than citing ChEMBL.

However, data often comes in a table, and won't have a real evidence text. It's not exactly clear whether BEL requires evidences for each statement, so for now a placeholder string saying "Retrieved from X" and an additional annotation called Database set to X will allow forward-compatibility. Use an identifiers.org namespace whenever possible for X.

Finally, with both the assay metadata and provenance, we get:

SET Citation = {"PubMed", "2153213"}
SET Evidence = "Retrieved from ChEMBL"
SET Database = "chembl"

SET AssayType = "B"
SET MeasurementType = "IC50"
SET MeasurementUnits = "nM"
SET MeasurementRelation = "="
SET MeasurementValue = "0.5"

SET Species = "9606"
SET Cell = "HEPG2"

a(CHEMBL:CHEMBL1487) =| act(p(UNIPROT:P04035), ma(GO:0004420))

Receptor Binding

This example will focus on the binding of zolpidem (CHEMBL911) to the GABA receptor alpha-5 subunit (CHEMBL5112, UniProt:A8K338, HGNC:GABRA5)

The binding of a chemical to a receptor is represented by the chemical causing a complex with the protein. Binding is typically measured with Ki.

SET AssayType = "B"
SET MeasurementType = "Ki"
SET MeasurementUnits = "nM"
SET MeasurementRelation = ">"
SET MeasurementValue = "15000"

SET Species = "9606"

a(CHEMBL:CHEMBL911) => complex(p(UNIPROT:A8K338), a(CHEMBL:CHEMBL911))

Zolipidem is not a very strong binder to the GABA receptor alpha-5 subunit, so it is unlikely we'll find an annotation as to its binding type.

Binding Type

  • Full agonists are able to activate the receptor and result in a strong biological response. The natural endogenous ligand with the greatest efficacy for a given receptor is by definition a full agonist (100% efficacy).
  • Partial agonists do not activate receptors with maximal efficacy, even with maximal binding, causing partial responses compared to those of full agonists (efficacy between 0 and 100%).
  • Antagonists bind to receptors but do not activate them. This results in a receptor blockade, inhibiting the binding of agonists and inverse agonists. Receptor antagonists can be competitive (or reversible), and compete with the agonist for the receptor, or they can be irreversible antagonists that form covalent bonds (or extremely high affinity non-covalent bonds) with the receptor and completely block it. The proton pump inhibitor omeprazole is an example of an irreversible antagonist. The effects of irreversible antagonism can only be reversed by synthesis of new receptors.
  • Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy).

To Do:

  • add full agonist example
  • add partial agonist example
  • add antagonist example

Allostery

In general, if allostery is not set, then it is assumed to be None.

Allosteric modulators do not bind to the agonist-binding site of the receptor but instead on specific allosteric binding sites, through which they modify the effect of the agonist. For example, benzodiazepines (BZDs) bind to the BZD site on the GABAA receptor and potentiate the effect of endogenous GABA.

  • Positive allosteric modulator
  • Negative allosteric modulator

Source: https://en.wikipedia.org/wiki/Receptor_(biochemistry)

When the binding type is set, we can also write a second statement with how the binding affects the activity of the receptor.

Basmisanil (CHEMBL3681419) is an inverse agonist of the GABA receptor alpha-5 subunit (UNIPROT:A8K338).

SET Citation = {"Patent", "US-8846719-B2"}

SET AssayType = "B"
SET MeasurementType = "Ki"
SET MeasurementUnits = "nM"
SET MeasurementRelation = "="
SET MeasurementValue = "445.47"

SET BindingType = "Inverse agonist"
SET Allostery = "Negative"

SET Species = "9606"

 # Basmisanil binds GABA receptor alpha-5
a(CHEBML:CHEMBL3681419) => complex(p(UNIPROT:A8K338), a(CHEMBL:CHEMBL3681419))

  # Binding of basmisanil decreases the activity of the receptor
complex(p(UNIPROT:A8K338), a(CHEMBL:CHEMBL3681419)) =| act(p(UNIPROT:A8K338))