Druggability is a term used in
drug discovery to describe a
biological target
A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
(such as a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
) that is known to or is predicted to bind with high affinity to a
drug. Furthermore, by definition, the binding of the drug to a druggable target must alter the function of the target with a therapeutic benefit to the patient. The concept of druggability is most often restricted to
small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...
s (low molecular weight organic substances)
but also has been extended to include
biologic medical products such as therapeutic
monoclonal antibodies.
Drug discovery comprises a number of stages that lead from a biological hypothesis to an approved drug. Target identification is typically the starting point of the modern
drug discovery process. Candidate targets may be selected based on a variety of experimental criteria. These criteria may include
disease linkage (mutations in the protein are known to cause a disease), mechanistic rationale (for example, the protein is part of a regulatory pathway that is involved in the disease process), or
genetic screen
A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens c ...
s in
model organisms.
Disease relevance alone however is insufficient for a protein to become a drug target. In addition, the target must be druggable.
Prediction of druggability
If a drug has already been identified for a target, that target is by definition druggable. If no known drugs bind to a target, then druggability is implied or predicted using different methods that rely on evolutionary relationships, 3D-structural properties or other descriptors.
Precedence-based
A protein is predicted to be "druggable" if it is a member of a
protein family for which other members of the family are known to be targeted by drugs (i.e., "guilt" by association). While this is a useful approximation of druggability, this definition has limitations for two main reasons: (1) it highlights only historically successful proteins, ignoring the possibility of a perfectly druggable, but yet undrugged protein family; and (2) assumes that all protein family members are equally druggable.
Structure-based
This relies on the availability of experimentally determined 3D structures or high quality homology models. A number of methods exist for this assessment of druggability but all of them consist of three main components:
#Identifying cavities or pockets on the structure
#Calculating physicochemical and geometric properties of the pocket
#Assessing how these properties fit a training set of known druggable targets, typically using machine learning algorithms
Early work on introducing some of the parameters of structure-based druggability came from Abagyan and coworkers
and then Fesik and coworkers,
the latter by assessing the correlation of certain physicochemical parameters with hits from an NMR-based fragment screen. There has since been a number of publications reporting related methodologies.
There are several commercial tools and databases for structure-based druggability assessment. A publicly available database of pre-calculated druggability assessments for all structural domains within the
Protein Data Bank
The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, ...
(PDB) is provided through the
ChEMBL
ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties.
It is maintained by the European Bioinformatics Institute (EBI), of the European Molecular Biology Laboratory ( EMBL), based at the Wel ...
's DrugEBIlity portal.
Structure-based druggability is usually used to identify suitable binding pocket for a small molecule; however, some studies have assessed 3D structures for the availability of grooves suitable for binding helical mimetics.
This is an increasingly popular approach in addressing the druggability of
protein-protein interactions.
Predictions based on other properties
As well as using 3D structure and family precedence, it is possible to estimate druggability using other properties of a protein such as features derived from the amino-acid sequence (feature-based druggability)
which is applicable to assessing small-molecule based druggability or biotherapeutic-based druggability or the properties of ligands or compounds known to bind the protein (Ligand-based druggability).
The importance of training sets
All methods for assessing druggability are highly dependent on the
training set
In machine learning, a common task is the study and construction of algorithms that can learn from and make predictions on data. Such algorithms function by making data-driven predictions or decisions, through building a mathematical model from ...
s used to develop them. This highlights an important caveat in all the methods discussed above: which is that they have learned from the successes so far. The training sets are typically either databases of curated drug targets;
screened targets databases (
ChEMBL
ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties.
It is maintained by the European Bioinformatics Institute (EBI), of the European Molecular Biology Laboratory ( EMBL), based at the Wel ...
,
BindingDB
BindingDB
is a public, web-accessible database of measured binding affinities, focusing chiefly on the interactions of proteins considered to be candidate drug-targets with ligands that are small, drug-like molecules. As of March, 2011, Bindi ...
,
PubChem
PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information (NCBI), a component of the National Library of Medicine, which is part of ...
etc.); or on manually compiled sets of 3D structure known by the developers to be druggable. As training sets improve and expand, the boundaries of druggability may also be expanded.
Undruggable targets
Only 2% of human proteins interact with currently approved drugs. Furthermore, it is estimated that only 10-15% of human proteins are disease modifying while only 10-15% are druggable (there is no correlation between the two), meaning that only between 1-2.25% of disease modifying proteins are likely to be druggable. Hence it appears that the number of new undiscovered drug targets is very limited.
A potentially much larger percentage of proteins could be made druggable if
protein–protein interaction
Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and th ...
s could be disrupted by small molecules. However the majority of these interactions occur between relatively flat surfaces of the interacting protein partners and it is very difficult for small molecules to bind with high affinity to these surfaces.
Hence these types of binding sites on proteins are generally thought to be undruggable but there has been some progress (by 2009) targeting these sites.
Chemoproteomics Chemoproteomics entails a broad array of techniques used to identify and interrogate protein- small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of allev ...
techniques have recently expanded the scope of what is deemed a druggable target through the identification of covalently modifiable sites across the proteome.
References
Further reading
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External links
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* {{cite web , url = http://tdrtargets.org/ , title = TDR Targets Database , publisher = The TDR Drug Targets Network
Drug discovery