What is drug discovery?
The pharmaceutical industry includes products borne out of drug discovery programmes, extensions to existing product lines, longstanding brand lines and generics, and prescription-only-medicines.
A major challenge for the pharmaceutical industry is the long and risky development process for new drugs; this is costly and can take over ten years from the laboratory to clinical trials. Typically, only around five out of 5,000 compounds that have been assessed at the preclinical stage will reach human clinical trials. Of these five, only one will eventually be approved by the regulatory authorities. The investment of time and cost in such processes places a significant strain on drug developers. Woodley BioReg provide early strategic advice in clinical, nonclinical, CMC/ manufacturing, and regulatory pathways to ensure clear routes and risk mitigation.
Drug discovery and screening overview
High-throughput screening methods help in selecting compounds which ideally only interfere with the chosen target, and no other related targets. Cross-screening is used to determine whether the “hits” against the chosen target will interfere with other related targets. If a compound “hits” unrelated targets it is likely that toxicity will be observed during clinical testing stage.
The output of early screening runs is very rarely a perfect drug candidate, but typically result in the identification of several compounds with some degree of activity. If these compounds share common chemical features and one or more pharmacophores can then be developed using a combination or hybrid approach.
Following screening, medicinal chemists use structure-activity relationships (SARs) to improve certain features of the lead compound including increased activity against the chosen target, reduced activity against unrelated targets, improved drug likeness, and ADME properties of the molecule. This process usually occurs through several iterative screening runs and leads to an improvement in the properties of the new molecular entities.
During the next stage, the candidate compounds undergo in vitro and in, vivo testing for activity in the disease model of choice.
- Synthesis of the lead compounds
- New analogues with improved potency
- Reduction in off-target activities
- Assessment and application of physiochemical and/or metabolic
properties indicating of reasonable in vivo pharmacokinetics
Following this, further optimisation occurs through chemical modification, modifications through structure-activity analysis (SAR), and structure-based design.
The latter stages of drug discovery requires process development to allow scale-up and technology transfer at a later date for commercial and GMP manufacture. Project management forms a key component of drug
development to manage and maintain budgets, timeframes, and commercial objectives.
The process is broadly split into three main areas, which are outlined below.
Drug discovery process
1. Discovery to Development Track
The drug discovery to development process is used by pharmaceutical companies to identify a target product profile (TPP). This establishes important clinical and CMC attributes, drives clinical plans, reflects the anticipated label, drives the company portfolio value and ranking, and guides decision-making.
2. Nonclinical Development
Nonclinical development involves nonclinical safety evaluations, development of appropriate safety profiles, identification of targets, identification of methods for monitoring toxicity and clinical blood drug levels, assessment of toxicity observed in preclinical models (predictive of toxicity in patients), exposure adequacy and safety margins for patient population, and indication involved.
3. Clinical Development
The final stage of drug discovery is the clinical development. The wide range of activities here include the provision of clinical trials, regulatory filings, agency meetings and approval of all documentation obtained during the course of the drug discovery to development process. Clinical development is critical in establishing product quality, safety, and efficacy.