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In search of the perfect assay description

Credit: Science biotech, CC BY-SA 4.0

Assays describe the experimental set-up when testing the activity of drug-like compounds against biological targets; they provide useful context for researchers interested in drug-target relationships. Version 33 of ChEMBL contains 1.6 million diverse assays spanning ADMET, physicochemical, binding, functional and toxicity experiments. A set of well-defined and structured assay descriptions would be valuable for the drug discovery community, particularly for text mining and NLP projects. These would also support ChEMBL's ongoing efforts towards an in vitro assay classification. This Blog post will consider the features of the 'perfect' assay description and provide a guide for depositors on the submission of high quality data.

ChEMBL's assays are typically structured with the overall aim, target, and methodThe ideal assay description is succinct but contains all the necessary information for easy interpretation by database users, as well as comparison between similar assays. Relevant parameters depend on the nature of the assay; for example, protein binding assays should include details of any protein sequence variation as well as other biological entities present in the assay (e.g. subcellular fractions). On the other hand, the drug concentration and route of administration are more relevant for the interpretation of ADMET assays. 

There are five assay types within ChEMBL: Binding (B), Functional (F), ADME (A), Toxicity (T), Physicochemical (P) as well as an Unclassified (U) type for assays that don't fit these groups. During curation, we map assays to the tested biological target. Our targets may be a defined molecular entity such as the single protein ABL kinase or a broader non-molecular target such as the whole organism E. coli. Most assays report a biological target, but exceptions include those exploring the physicochemical properties of drugs or their absorption, distribution, metabolism, and excretion where a defined target may not be relevant, or known.

Typical structure of ChEMBL assays

Binding (Type B) and functional (Type F) assays

Binding and functional assays test the binding or activity of drug-like compounds at defined biological targets and comprise the bulk of assays within ChEMBL. It’s important to capture all target features that could impact drug activity within these assay descriptions. This includes protein variation, fusions and isoform information.

Assay descriptions reporting molecular targets. In addition to the overall aim, target and method, biological entities (cell extracts, tissues) and/or expression information (bacteria, cell-line, purified protein) and protein variation (wild-type or mutated) should be included. The assays above are: type B; row 1, type F; row 2type F; row 3, and type F; row 4.

For assays performed in higher level systems such as cells, tissues or whole organisms, phenotypes such as drug-resistance and the targeted biological pathways, drug delivery method (e.g. route, dose) and model system are important and should be covered in the assay description 

Assay descriptions reporting non-molecular targets. For higher-level systems such as cells, tissues, and organisms, relevant dosing information and phenotypes (e.g. drug-sensitive/resistant) should be included. 

Physicochemical (type P) assays 

Physicochemical assays provide valuable information on drug properties, such as solubility and lipophilicity, and are relevant to drug design and formulation. Inclusion of parameters such as the pH, temperature, and solvent in the assay description improves their usability.

A physicochemical assay.

ADME (type A) and toxicity (type T) assays

Pharmacokinetic studies provide an insight into the action and processing of a drug in vivo. Inclusion of the dose, route of administration, time of measurement, model system and sampled tissue in the corresponding assay descriptions allows researchers to explore the ADME(T) properties of drugs. A set of well-defined CMax assays, for example, will include the dose, dose unit, route of administration and time whereas biodistribution assays should record the target tissue where known and relevant. 

ADMET assays including metadata such as dose, tissue and route of administration. In these cases, a molecular target is not annotated.

Safety studies form a critical part of the drug development process and identifying the potential for toxicity/adverse side effects at the earliest stage during a drug discovery programme can save time and resources. Furthermore, publication of late-stage animal toxicity assays can provide an insight into the mechanism of drug toxicity. A good assay description with record the adversely affected target tissue or biological process as well as the nature of the adverse effect.

Toxicity assays: Annotation of the target tissue (kidney) provides valuable safety-related data. 

We hope that carefully captured assay descriptions will increase the usability of ChEMBL assays in future, and also support our efforts to classify in vitro assays and facilitate the rapid and accurate mapping of assays to the correct ChEMBL target. Complex datasets containing multiplex assays may require further annotation and metadata for their interpretation. Additional metadata can be submitted for both the assay set-up and bioactivity results in the ASSAY_PARAMETERS and ACTIVITY_PROPERTIES tables. More details on these tables will follow in a future Blog post. 

Questions? Get in touch in the Helpdesk with any further questions or browse our assays.


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