Drug discovery has evolved in the last 50–60 years from a purely phenotypic screening approach (compound libraries subjected to systems-based assays to identify compounds with biological effects) towards a target-based approach, whereby a rational hypothesis-based design of compounds is created through the use of technologies such as molecular biology understanding, structure-based drug design, combinatorial and parallel chemistry and human genome sequencing. Nevertheless, the discovery of first-in-class drugs is still dependent on these two differing approaches.
The stages of drug discovery and development of small molecules can be divided into three main phases and taking an idea to an approved medicine can take 10–15 years of research and development and cost up to a billion US dollars:
Drug discovery : Pharmacological characterization of small molecules or larger molecules such as antibodies or peptides (see Chapter 8 ) to choose a lead drug candidate.
Preclinical development : Regulatory safety and toxicological testing (see Chapter 9 ), along with development work to choose the appropriate route of administration and formulation to deliver the drug.
Clinical development: Phase I studies to evaluate safety, followed by clinical trials in patients to select appropriate doses and to evaluate efficacy and safety.
For ease of understanding, the different phases of drug development are discussed in a linear way ( Fig. 7.1 ). However, in reality the knowledge gained within each phase provides the basis of an iterative approach to optimize the development of a new medicine as often the first candidate selected for evaluation is not the drug finally approved, with many thousands of compounds often needing to be tested to ultimately find the best compound.
The Drug Discovery Phase
The identification of a target occurs through the intelligence and knowledge of the research team building on evidence that a particular protein (e.g. receptor, enzyme, transport protein, signalling molecule) or mediator/neurotransmitter is involved in a pathophysiological process. Clearly, it is important to demonstrate that the target is expressed in humans, and better still that the target is differentially expressed in cells or tissue from patients with the disease that the drug is ultimately trying to target (e.g. the expression of an antigen on a cancer cell that is not found on healthy cells, or an enzyme found in bacteria or parasites that is not found in mammalian cells) to improve the likelihood of finding a drug with a wide therapeutic window. Various cell-based expression assays, in vitro functional assays, and in vivo disease modelling assays are used, or discerned from literature searches to better understand the apparent importance of the target. Given the high costs of developing new medicines, in most cases, the research group identifying new molecules that interact with the target will have some form of intellectual property protecting their intellectual investment in identifying new drugs to provide them with a period of exclusivity to market their new medicine and thus be able to both recoup their discovery and development costs and make a profit. Without this incentive new medicines would not be made.
Identification of a lead candidate
After a biochemical target has been decided, the research team will search for lead compounds . The human form of the target protein will be cloned and assays developed, so that the functional activity of the target can be measured in the presence of lead compounds for potency and efficacy and other basic pharmacological characteristics such as affinity and selectivity (see Chapter 3 ).
Several approaches might be undertaken to find or create lead compounds:
Compound screening of large libraries of chemical entities (>1 million compounds).
Structural knowledge of known ligands (endogenous or existing synthetic, plant/insect/marine organism-based chemicals, etc.).
The use of X-ray crystallography and other techniques to provide knowledge of the three-dimensional structure of the target that allows for rational computer-based modelling to identify novel lead compounds and to help with optimizing structure-activity relationships.
Lead compounds that show desired actions in vitro are referred to as hits . Their chemical structures and physiochemical characteristics are then further explored to improve the features of the molecule such as affinity and selectivity for a target, metabolic stability, solubility and duration of action. Through an iterative process and testing of a limited number of compounds in vivo for bioavailability and acute toxicity, a small number of lead compounds are then tested in a range of different in vitro and in vivo functional assays, mimicking aspects of the human condition. Various in vitro safety and toxicology assays will also be employed to ascertain whether any of the lead compounds might have unwanted side effects that would lead to them being rejected as candidates before going into the next regulatory stage of development, which is a particularly expensive part of the process.