Discovery Process
Discovering the drugs of tomorrow is a complicated, high risk and lengthy process. From the initial concept for a biological drug target through to creating a drug that is considered safe to begin human testing, takes as much as 6 years, involves up to 100 dedicated scientists from a multitude of disciplines and costs approximately $25m per drug. While each drug discovery organization has its own individual processes, the overall concept of drug discovery is based around the same principles.
Target Identification
Scientists start the quest for finding new medicines by identifying the molecular causes of disease. Modern technology allows scientists to "screen" the genes or proteins that are uniquely expressed or absent in diseased tissue. Some of these genes are not actually involved in the disease, while others are part of biological processes not amenable to drug intervention. But some are identified as potential suspects in the cause or symptoms of the disease. This overall process is known as target identification. Target identification is an enormous undertaking and involves the input of industry scientists as well as academic and government scientists, all dedicated to finding answers to some of modern medicines most complicated questions.
Target Validation
Once molecular biologists have identified a gene or a collection of genes that seem to be altered in a specific disease, biologists then try to validate and understand the role of that gene in the disease. This process, known as target validation, involves a number of different technologies including that of genetic modification. Animal models and in vitro experiments are used to verify a genes involvement in the disease. Scientists use techniques such as removing or over expressing gene’s and their products in the genome of laboratory animals and study the biological consequences to the animal. Additionally scientists use other pharmacological methods to assess the relevance of a gene and its protein product in the disease and its symptoms. The validation phase is critical to the downstream discovery process. The more scientists are assured of the biological targets role in the disease, the more comfortable they are in investing the significant time and money involved to discover a medicine that can modify the activity of the target and subsequently modify the disease or its symptoms
Assay Development
Once a biological target believed to be appropriate for medicinal modulation is identified, an "assay" must be developed in which the ability to chemically modify the targets biological activity can be tested. At this point biologists and screening scientists work together to design experiments that can be performed by robots in ultra small volume and at high throughput, such that hundreds of thousands of compounds can be tested in the biological experiment each day.
High Throughput Screening
The role of chemistry in drug discovery starts with the existence of the "compound library". This is a library of literally hundreds of thousands of small molecule chemicals in large robotic storage devices, each often completely unique to the parent companyIt is the overwhelming numbers of compounds within the libraries (as many as 1,000,000+), which force the need for High Throughput Screening (HTS). Screening almost 1 million individual compounds against just one biological target manually is an extremely inefficient method. Modern technology has allowed us to roboticize the entire process and to miniaturize it. In this way it is now possible to test approximately 100,000 compounds against one biological target per day and visualize “live” results of the impact of each chemical on the target. In this way we can see which of the chemicals affects the target and therefore which should be pursued further. Compounds that modify the biological target are called "hits" and form the starting point for the next phase of the drug discovery process.
Hit to Lead Chemistry
As many as several hundred chemicals can be identified as “hits” from the HTS process. While they may modify the biological target these compounds are, at this stage, very basic and crude. If we consider the biological target as a lock and the compound as a key, these “hits” might well fit the lock but may not fully allow the lock to be opened or indeed closed. Additionally many of these newly identified compounds might be non-specific, that is they may be capable of opening many other biological locks, and as such they are not optimal for further development since they would likely cause side effects. Yet other compounds might open the lock, but it might take vast amounts of compound to open just one lock in a very inefficient manner, alternatively they may open or close the lock too slowly or irreversibly. Hit to lead chemistry assesses each of the “hits” based on these types of criteria, and discards the ones which are considered sub-optimal. The ultimate purpose of hit to lead chemistry is to whittle down the number of compounds to one or two which are as optimal for the biological target as possible, and which display the properties most desired for the medicine. Once the lead compounds have been identified they are handed over to medicinal chemists for the process of modification and optimization.
Lead Optimization
Highly trained medicinal chemists take the identified lead compounds and start to make methodical changes to all parts of their structure in an effort to make the compound better fit the specific biological target and open or close it more efficiently. As each iterative change is made, biologists take the newly created compound and assess its biological activity, firstly in test-tube experiments, and subsequently in animal models of disease. The biologists feed the results back to the chemists who use this data to drive the next round of modification. After numerous iterative alterations the biological activity is optimized and a new experimental medicine is created. The process of lead optimization can take as much as two years and in this time as many as xxx compounds might be made and tested.
Biopharmaceuticals
In the past 15 years or so the focus of the pharmaceutical industry has gradually shifted from the traditional platforms of small molecules and vaccines, to include biopharmaceuticals. Biopharmaceuticals are complicated protein-based molecules that can function as agonists and deliver a positive signal, antagonists able to block the targets function, or they can replace or block a missing or malfunctioning protein. Proteins are particularly useful for blocking protein-protein interactions such as receptor-ligand interactions due to their high affinity and specificity. As for small molecules the process starts with a screening procedure. Libraries containing 1 billion plus antibody fragments are used to assess in vitro target binding. These libraries can be screened at a rate of >1000 clones per day in cell-based assays. Typically between 5,000 and 50,000 clones will be screened for any one campaign. Like their small molecule counterparts, biotherapeutics are also optimized to enhance the affinity and specificity of the agent for its biological target, to modify the mechanism of interaction or to alter the in vivo uptake or clearance of the molecule. The affinity of an antibody can be increased by engineering the complementarity determining region using technologies such as phage or ribosome display. If the lead antibody is rodent in origin it can be humanized by grafting specific portions of the rodent antibody onto human constant domains, thus rendering the antibody less immunogenic in humans. Additionally, proteins are optimized for maximum expression in cellular systems, maximum product quality, homogeneity, stability and solubility.Discovery Research at Wyeth places a significant emphasis on the growing promise of biopharmaceutical therapies. As much as 25% of the novel therapeutics we transition into development annually are biopharmaceuticals, these can be monoclonal antibodies, antibody fragments or proteins. To accomplish this degree of productivity in the continuously innovative environment of biopharmaceutical drug discovery, we have a group dedicated to the discovery and development of biopharmaceuticals. This group has access to state of the art technologies which allow for continuous improvements in this ever-expanding field.
Pre-clinical Safety
Safety is one of the main focuses as new drugs are discovered and developed. Thus, as the most biologically active compounds are identified, so too are they assessed for how they can be administered, how rapidly they are metabolized, whether they are evenly distributed around the body and whether they cause any toxicological liability. It is essential that as much as possible is learnt of the biological profile of the experimental drug at this stage, since the next step is to place the drug into humans