Cambridge MedChem Consulting

Drug Discovery Stage definitions

Whilst the Drug Discovery process is continuous and can vary depending on target it is often useful to split the process into stages with key milestones and targets clearly defined and met before a project moves from one stage to the next.

Target Identification

Demonstration that the potential molecular target is present in human or in parasite/infective agent. At this point it is usual to identify an assay to evaluate modulation of the target and determine the feasibility of screening.

The Centre for Therapeutic Target Validation platform brings together information on the relationships between potential drug targets and diseases. The core concept is to identify evidence of an association between a target and disease from various data types.

A target can be a protein, protein complex or RNA molecule, but we integrate evidence through the gene that codes for the target. In the same way, we describe diseases through a structure of relationships called the Experimental Factor Ontology (EFO) that allows us to bring together evidence across different but related diseases.The platform supports workflows starting from either a target or disease and presents the evidence for target – disease associations in a number of ways through association and evidence pages.

DisGeNET is a discovery platform integrating information on gene-disease associations (GDAs) from several public data sources and the literature doi.

The current version contains (DisGeNET v3.0) contains 429111 associations, between 17181 genes and 14619 diseases, disorders and clinical or abnormal human phenotypes.

Target Validation

Proof that modulation of the identified target in a model system has the desired impact on biological activity and can be linked to therapeutic utility. This might be achieved by identification of genetic mutations in the human population for example CCR5 mutations and HIV, gene knock-out studies in mice, or siRNA experiments, for example siRNA and neuropathic pain. There may also be known small molecules that exert the desired effect but perhaps with a sub-optimal profile. It may be possible to identify potential liabilities at this point or key off-targets issues. Screening assay in place together with functional screen. If you are using literature data for target validation your mantra should be "Trust but verify".

This is an absolutely critical step, almost everything else can be fixed.

Hit Identification

Identification of the starting point for the drug discovery program, this might be a natural ligand or a molecular from the literature, however it is more likely to be derived from a screening campaign. A wide variety of screening technologies are available from high-throughput screening, fragment-based screening to virtual screening.

“The single most important factor determining the likelihood of success of a project is the quality of the starting lead”, Anon

Whilst most screens will identify many potential hits the critical step is to validate the hit, the degree of validation may depend on the screening technology (e.g. fragment hits may be too weak to show functional activity) but the list below gives some ideas.

Lead Identification

Demonstration that one or more of the small molecule hits has the potential to provide a series that could be optimised to afford a candidate. The following list provides some thoughts

All key in vitro assays in place and in vivo efficacy models identified, strategy for predicting clinical dose in place (Remember an in vivo efficacy model in which you block the effect of an applied agonist can obviously be manipulated by changing the dose of agonist).

Lead Optimisation

Optimisation of one or more of the compounds from the lead series identified into a clinical development candidate, focus on:-

Some studies may require labelled compound.

Candidate Selection

All compounds are unique and this list should only regarded as a guideline. See also Preclinical Checklist

Updated 2 August 2018