The Drug Discovery Process: From the Target to Beyond

A drug is any chemical taken that affects the way your body works. These could be alcohol, nicotine or caffeine. A drug has to be able to pass from your body to your brain and change messages that your brain cells are sending to each other and the rest of your body by interfering with the brains chemical signals. New drugs are needed for many reasons.

Firstly, to downstream health costs, cost of therapy costs to individual countries and to sustain industrial activity. Drugs can either be labelled as generic or branded. Generic medicine is a group of medicines that have similar actions and similar sounding names. Branded drugs are drugs that were generic but now have been given a brand name by a company. The names of these branded drugs are easily marketable and memorable for consumer ease. The drug discovery process is made up of different stages and is the first part of a chain that takes a discovered drug through to distribution.

There are two distinct phases to discovering and commercialising medicine. The first phase is the discovery phase. This involves pre-discovery which is when lots of information is gathered about a certain disease to be able to understand the nature of the disease and therefore how to treat it. The next step is to identify the target by choosing a molecule in the body to target with a drug and this is often a protein. The next step is to test the target and confirm its role in the disease which then leads to the drug discovery step to find a ‘lead compound’ that could become a drug. After the lead compound has been found, early safety tests need to be done on it such as pharmacokinetics using experiments or computer modelling.

The structure of the lead compound now needs to be improved by formulation and delivery mechanism. The development phase occurs after the potential drug and mechanisms have been identified. This includes pre-clinical testing to determine whether the drug is appropriate to test on humans. Once the drug has proved safe enough for human testing, a CTX (clinical trial exceptions) application needs to be put through so that the 3 phases of clinical trials can begin. Phase 1 clinical trial is when a small group of healthy human volunteers test the drug. Phase 2 clinical trial is when the drug is tested on a small group of patients and phase 3 is when a large group of patients with the disease are tested to show efficacy and safety. One the drug has proved successful and safe for a majority of the patients, marketing and manufacturing can occur on a full-scale. The drug still needs to undergo constant monitoring whilst in use (phase 4 trials).

The drug discovery process begins with choosing a disease. Pharmaceutical companies tend to avoid diseases that affect a minority of people as it is expensive to research and develop new drugs. Diseases that affect only the third world countries will often be avoided due to their low economic status and pharmaceutical companies concentrate on developing drugs for diseases that are prevalent in developed countries and aim to develop better compounds with better properties than existing drugs. A majority of the research is put into diseases such as cancer, depression, diabetes, obesity and cardiovascular diseases rather than tropical diseases unless the tropical diseases start to have an impact on richer countries.

The orphan drug act was passed in 1983 which encourages pharmaceutical companies to discover drugs for diseases affecting less than 200,000 people in the US. This is beneficial for the company as they will be able to market it without competition for 7 years. Once a disease has been chosen it is then suitable to choose a drug target. This is a target molecule that a drug needs to find and act on. It Is often a protein molecule such as an enzyme. It is essential for the disease being treated to be understood on a molecular level using genomics, bioinformatics and proteomics. Researchers need to look for proteins or mRNA that have been expressed/not expressed in a disease using comparative gene expression assays or comparative proteomic profiles. They need to identify genes or proteins essential for the infectious agents or gene/protein modifications associated with the disease. Regulatory pathways required for the disease process need to be found.

Experimental techniques such as NMR, EM, Protein Data Bank and Swiss Prot are used to predict protein structures. Prediction of protein structures is important to fill any gaps between known sequences and structures and for rational drug design. X-ray crystallography and nuclear magnetic resonance (NMR) are used to solve the structure of 3D proteins. X-ray crystallography can be used on a protein of any size and was the first to be used to identify the 3D structure of a protein. When an electron is hit by x-rays the electron starts vibrating and secondary beams are scattered in all directions.

The scattering is secondary radiation which will interact and cause interference. The scattering of a molecule Is dependant on its structure therefore if we know the phases of a scattered molecule, we can calculate the structure. After the drug target has been chosen, it is important to identify a bioassay. A bioassay is a test used to determine biological activity. Choosing the appropriate bioassay is crucial to the success of drug research. The test should be quick and relevant as there are a large number of compounds needed to be analysed. The test is done in vitro first, which are cheaper, easier and less controversial than in vivo tests. In vivo tests need to check drug interactions and pharmacokinetics. In vitro tests involve isolated specific tissues and cells or enzymes and are tested on in a laboratory.

Antibacterial drugs are tested in vitro. In vivo tests are tested on animals in clinical conditions to observe symptoms. The animal is treated with the drug to see whether the symptoms are alleviated. Most of the time the validity of the testing procedure is clear and easy but other cases display a more difficult test e.g. antipsychotic drugs. High throughput screening (HTS) involves the in vitro testing to be automated so that a large number of tests can be carried out in a short period of time. The tests should show an easily measurable effect such as cell growth or enzyme reaction.

Once the biological activity has been identified, the ‘lead compound’ needs to be determined. The lead compound is a structure that has some activity against the chosen target but not yet good enough to be the drug itself. This can be done by identifying structure-activity-relationships (SAR’s). The pharmacophore contains the structural features directly responsible for activity and the lead compound can be identified when the pharmacophore is identified. Knowing this can optimise the structure and improve interactions with the target. The pharmacokinetics and pharmacodynamics of the drug should be determined.