Datasets

In the CC nomenclature, a dataset is determined by:

1. One coordinate.
2. One (typically) or multiple (eventually) sources having the same type of (mergeable) data.
3. A processing procedure yielding signatures type 0.

Levels, coordinates and datasets

The CC is divided into five levels of increasing complexity:

Level	Name	Description
A	Chemistry	Chemical properties of the compounds.
B	Targets	Chemical-protein interactions.
C	Networks	Higher-order effects of small molecules.
D	Cells	Readouts of compound cell-based assays.
C	Clinics	Clinical data of drugs and environmental chemicals.

In turn, each level is divided into 5 sublevels or coordinates representing different aspects of the data. Each sublevel has an exemplary dataset, as described below:

Coordinate	Name	Description
A1	2D fingerprints	Binary representation of the 2D structure of a molecule. The neighbourhood of every atom is encoded using circular topology hashing.
A2	3D fingerprints	Similar to A1, the 3D structures of the three best conformers after energy minimization are hashed into a binary representation without the need for structural alignment.
A3	Scaffolds	Largest molecular scaffold (usually a ring system) remaining after applying Murcko’s pruning rules. Additionally, we keep the corresponding framework, i.e. a version of the scaffold where all atoms are carbons and all bonds are single. The scaffold and the framework are encoded with path-based 1024-bit fingerprints, suitable for capturing substructures in similarity searches.
A4	Structural keys	166 functional groups and substructures widely accepted by medicinal chemists (MACCS keys).
A5	Physicochemistry	Physicochemical properties such as molecular weight, logP, and refractivity. Number of hydrogen-bond donors and acceptors, rings, etc. Drug-likeness measurements e.g. number of structural alerts, Lipinski’s rule-of-5 violations or chemical beauty (QED).
B1	Mechanism of action	Drug targets with known pharmacological action and modes (agonist, antagonist, etc.).
B2	Metabolic genes	Drug metabolizing enzymes, transporters, and carriers.
B3	Crystals	Small molecules co-crystalized with protein chains. Data is organized according to the structural families of the protein chains.
B4	Binding	Compound--protein binding data available in major public chemogenomics databases. Data mainly comes from academic publications and patents. Only binding affinities below a class-specific threshold are kept (kinases ≤ 30 nM, GPCRs ≤ 100 nM, nuclear receptors ≤ 100 nM, ion channels ≤ 10 uM and others ≤ 1 uM).
B5	HTS bioassays	Hits from screening campaigns against protein targets (mainly confirmatory functional assays below 10 uM).
C1	Biological roles	Ontology terms associated with small molecules with recognized biological roles, such as known drugs, metabolites and other natural products.
C2	Metabolic network	Curated reconstruction of human metabolism, containing metabolites and reactions. Data is represented as a network where nodes are metabolites and edges connect substrates and products of reactions.
C3	Canonical pathways	Canonical pathways related to the known receptors of compounds (as recorded in B4). Pathways are assigned via a guilt-by-association approach, i.e. a molecule is related to a pathway if at least one of the molecule targets is a member of it.
C4	Biological processes	Similar to C3, biological processes from the gene ontology are associated with compounds via a guilt-by-association approach from B4 data. All parent terms are kept, from the leaves of the ontology to its root.
C5	Interactomes	Neighborhoods of B4 targets are collected by inspecting several large protein-protein interaction networks. A random-walk algorithm is used to obtain a robust measure of 'proximity' in the network.
D1	Gene expression	Transcriptional response of cell lines upon exposure to small molecules. A well-documented reference dataset of gene expression profiles is used to map all compound profiles using a two-sided gene set enrichment analysis.
D2	Cancer cell lines	Small molecule sensitivity data (GI50) of a panel of 60 cancer cell lines.
D3	Chemical genetics	Growth inhibition profiles in a panel of ~300 yeast mutants. Data are combined with yeast genetic interaction data so that compounds can be assimilated to genetic alterations when they have similar profiles.
D4	Morphology	Changes in U-2 OS cell morphology measured after compound treatment using a multiplexed-cytological cell painting assay. 812 morphology features are recorded via automated microscopy and image analysis.
D5	Cell bioassays	Small molecule cell bioassays reported in ChEMBL, mainly growth and proliferation measurements found in the literature.
E1	Therapeutic areas	Anatomical Therapeutic Chemical (ATC) codes of drugs. All ATC levels are considered.
E2	Indications	Indications of approved drugs and drugs in clinical trials. A controlled medical vocabulary is used.
E3	Side effects	Side effects extracted from drug package inserts via text-mining techniques.
E4	Disease phenotypes	Manually curated relationships between chemicals and diseases. Chemicals include drug molecules and environmental substances, among others.
E5	Drug-drug interactions	Changes in the effect of a drug when it is taken together with a second drug. Drug-drug interactions may alter pharmacokinetics and/or cause side effects.

Each of the coordinates can contain an arbitrary number of datasets. All datasets are fully described in the PostGreSQL database, and searchable at the CC web app (⚠ not done yet). They receive a numbered coding (e.g. A1.001).

Dataset characteristics

This is how we define a dataset:

Column	Values	Description
Code	e.g.A1.001	Identifier of the dataset.
Level	e.g. A	The CC level.
Coordinate	e.g.A1	Coordinates in the CC organization.
Name	2D fingerprints	Display, short-name of the dataset.
Technical name	1024-bit Morgan fingerprints	A more technical name for the dataset, suitable for chemo-/bio-informaticians.
Description	2D fingerprints are...	This field contains a long description of the dataset. It is important that the curator outlines here the importance of the dataset, why did he/she make the decision to include it, and what are the scenarios where this dataset may be useful.
Unknowns	True/False	Does the dataset contain known/unknown data? Binding data from chemogenomics datasets, for example, are positive-unlabeled, so they do contain unknowns. Conversely, chemical fingerprints or gene expression data do not contain unknowns.
Discrete	True/False	The type of data that ultimately expresses de dataset, after the pre-processing. Categorical variables are not allowed; they must be converted to one-hot encoding or binarized. Mixed variables are not allowed, either.
Keys	e.g. CPD (we use @afernandez Bioteque nomenclature). Can be NULL.	In the core CC database, most of the times this field will correspond to CPD, as the CC is centred on small molecules. It only makes sense to have keys of different types when we do connectivity attempts, that is, for example, when mapping disease gene expression signatures.
Features	e.g. GEN (we use Bioteque nomenclature). Can be NULL.	When features correspond to explicit knowledge, such as proteins, gene ontology processes, or indications, we express with this field the type of biological entities. It is not allowed to mix different feature types. Features can, however, have no type, typically when they come from a heavily-processed dataset, such as gene-expression data. Even if we use Bioteque nomenclature to the define the type of biological data, it is not mandatory that the vocabularies are the ones used by the Bioteque; for example, I can use non-human UniProt ACs, if I deem it necessary.
Exemplary	True/False	Is the dataset exemplary of the coordinate. Only one exemplary dataset is valid for each coordinate. Exemplary datasets should have good coverage (both in keys space and feature space) and acceptable quality of the data.
Public	True/False	Some datasets are public, and some are not, especially those that come from collaborations with the pharma industry.

See the PostgreSQL database for more information.

Dataset pre-processing

Dataset pre-processing refers to everything that from downloaded/calculated/user-defined data until Signature Type 0. Pre-processing can be of very different complexity:

Here is where most of the SB&NB research happens. For now, dataset pre-processing is organized in a rather independent structure, i.e. each dataset receives its pre-processing scripts.

There are two mandatory files:

• run.py
• README.md