Druggability

Druggability is a term used in drug discovery to describe a biological target (such as a protein) 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 molecules (low molecular weight organic substances) but also has been extended to include biologic medical products such as therapeutic monoclonal antibodies. Druggability is a term used in drug discovery to describe a biological target (such as a protein) 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 molecules (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 screens in model organisms. Disease relevance alone however is insufficient for a protein to become a drug target. In addition, the target must be druggable. 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. 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. 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: 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 (PDB) is provided through the ChEMBL'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. 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).