An introduction to the drug discovery process
The drug discovery process underpins the entire pharmaceutical industry, encompassing the early stages of research from target discovery and validation, right through to the identification of a drug candidate or lead compound. Initial identification of small therapeutic candidates comes about via a variety of streams. Research can lead to new insights into disease processes that highlight novel pathways for which drugs can be developed to intervene. Alternatively, companies conduct large scale trial and error based programs in order to identify molecular compounds that may be of interest. This is the process most often performed during initial lead discovery, with a view to take novel compounds right the way through to preclinical and clinical trials. Thoroughly calculated risk analysis at this point can increase the chances of success when investments into a lead are made.
Step 1 – Target identification and Validation
Target identification and validation kicks off the whole drug discovery process. Naturally occurring cellular or modular structures that appear to play an important role in pathogenicity or disease progression are normally targets for therapeutics. A good target needs to be efficacious, safe and be accessible by the drug molecule/meet clinical needs of the prospective patient.
Following identification of the drug target, a systematic validation approach should be adhered to for the mode of action of lead candidate to be assessed for efficacy. The approach itself depends on the therapeutic area, but has a set of general principles that include disease association, preclinical evidence in key cells, preclinical evidence in intact systems (i.e. transgenic animals), and literature survey and competitor information.
Step 2 – Hit identification and Validation
The obvious next step is to identify whether the small molecule leads have the desired effect against the identified targets. There are a number of approaches by which hits can be identified, including high-throughput screening, knowledge-based approaches, and virtual screening. Validation of hits is required following initial screening, and again there are a few options to choose from.
Step 3 – Moving from a hit to a lead
After a number of hit series have been established, the aim at this point is the refinement of each hit series in order to produce more selective compounds. Multiple series should be worked on in tandem, as it is likely that some hit series will fail, often due to particular characteristics of the series. Focusing on multiple structurally different sets of hit series will help to offset this possibility.
Step 4 – Lead Optimization
At this stage, the aim is to maintain the desired properties of lead compounds while improving on possible deficiencies of their structures, with a view to produce a preclinical drug candidate. This stage can be used to find out whether your drug metabolizes in the right area of the body, or whether there are currently any side effects that are cause for concern. For this process, an integrated approach is recommended. The combination of specialists in computational chemistry, medical chemistry, drug metabolism, and other areas can provide unique insights into this late stage of the process.
Step 5 – Late Lead Optimization
Before progression to preclinical and clinical trials, late stage optimization, in which further pharmacological safety of a lead compound is assessed, is a vital step. If this stage is overlooked, problems in efficacy, pharmacokinetics, and safety are more likely to occur later on in drug development. Safety optimization is a core stage, the aims are to identify and progress the leads with the best overall safety profile, remove the most toxic leads, and establish a well-characterized hazard and translational risk profile to enable further in vitro tests.
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