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Revision as of 05:18, 16 February 2009 by Radagast83 (talk | contribs) (No clear consensus for merger)(diff) ← Previous revision | Latest revision (diff) | Newer revision → (diff)In medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed.
In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery. A new approach has been to understand how disease and infection are controlled at the molecular and physiological level and to target specific entities based on this knowledge.
The process of drug discovery involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy. Once a compound has shown its value in these tests, it will begin the process of drug development prior to clinical trials.
Despite advances in technology and understanding of biological systems, drug discovery is still a long process with low rate of new therapeutic discovery. Information on the human genome, its sequence and what it encodes has been hailed as a potential windfall for drug discovery, promising to virtually eliminate the bottleneck in therapeutic targets that has been one limiting factor on the rate of therapeutic discovery. However, data indicates that "new targets" as opposed to "established targets" are more prone to drug discovery project failure in general. This data corroborates some thinking underlying a pharmaceutical industry trend beginning at the turn of the twenty-first century and continuing today which finds more risk aversion in target selection among multi-national pharmaceutical companies.
Targets: New and Established
The definition of "target" itself is something debated within the pharmaceutical industry. However, the distinction between a "new" and "established" target can be made without a full understanding of just what a "target" is. This distinction is typically made by pharmaceutical companies engaged in discovery and development of small molecule therapeutics.
"Established targets" are those for which there is a good scientific understanding, supported by a lengthy publication history, of both how the target functions in normal physiology and how it is involved in human pathology. This does not imply that the mechanism of action of drugs that are thought to act through a particular established targets is fully understood. Rather, "established" relates directly to the amount of background information available on a target, in particular functional information. The more such information is available, the less investment is (generally) required to develop a therapeutic directed against the target. The process of gathering such functional information is called "target validation" in pharmaceutical industry parlance. Established targets also include those that the pharmaceutical industry has had experience mounting drug discovery campaigns against in the past; such a history provides information on the chemical feasibility of developing a small molecular therapeutic against the target and can provide licensing opportunities and freedom-to-operate indicators with respect to small molecule therapeutic candidates.
In general, "new targets" are all those targets that are not "established targets" but which have been or are the subject of drug discovery campaigns. These typically include newly discovered proteins, or proteins whose function has now become clear as a result of basic scientific research.
The majority of targets currently selected for drug discovery efforts are proteins. Two classes predominate: G-protein-coupled receptors (or GPCRs) and protein kinases.
Screening and Design
The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening (HTS), wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor (see antagonist and agonist): if the target is a protein kinase, the chemicals will be tested for their ability to inhibit that kinase.
Another important function of HTS is to show how selective the compounds are for the chosen target. The ideal is to find a molecule which will interfere with only the chosen target, but not other, related targets. To this end, other screening runs will be made to see whether the "hits" against the chosen target will interfere with other related targets - this is the process of cross-screening. Cross-screening is important, because the more unrelated targets a compound hits, the more likely that off-target toxicity will occur with that compound once it reaches the clinic.
It is very unlikely that a perfect drug candidate will emerge from these early screening runs. It is more often observed that several compounds are found to have some degree of activity, and if these compounds share common chemical features, one or more pharmacophores can then be developed. At this point, medicinal chemists will attempt to use structure-activity relationships (SAR) to improve certain features of the lead compound:
- increase activity against the chosen target
- reduce activity against unrelated targets
- improve the "drug-like" or ADME properties of the molecule.
This process will require several iterative screening runs, during which, it is hoped, the properties of the new molecular entities will improve, and allow the favoured compounds to go forward to in vitro and in vivo testing for activity in the disease model of choice.
While HTS is a commonly used method for novel drug discovery, it is not the only method. It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon (so-called "me too" drugs). Other methods, such as virtual high throughput screening, where screening is done using computer-generated models and attempting to "dock" virtual libraries to a target, are also often used.
Another important method for drug discovery is drug design, whereby the biological and physical properties of the target are studied, and a prediction is made of the sorts of chemicals that might (eg.) fit into an active site. Novel pharmacophores can emerge very rapidly from these exercises.
Once a lead compound series has been established with sufficient target potency and selectivity and favourable drug-like properties, one or two compounds will then be proposed for drug development. The best of these is generally called the lead compound, while the other will be designated as the "backup".
See also
- Drug Discovery Hit to Lead
- Drug development
- Pre-clinical development
- Protein structure prediction
- Drug design
- Rational drug design
- Compound management
- Bioinformatics
- Cheminformatics
- Biomedical informatics
- Orphan drug
- Pharmaceutical company
- Physiologically-based pharmacokinetic modelling
- Simcyp Simulator
- Pharmacogenetics
- Simulations Plus
Notes
- this requires substantiation with one or more reputable sources from the time of enthusiasm following "completion" of the human genome sequence
- Drug Discovery & Development, October 2005, reporting on industry trends in 2003–2005
References
1. Shayne Cox Gad (2005), Drug Discovery Handbook, Wiley-Interscience, ISBN 0-471-21384-5
2. Madsen U. (2002), Textbook of Drug Design and Discovery, CRC, ISBN 0-415-28288-8
External links
- In Focus "Medical Research involving Minors: Medical, legal and ethical aspects" (German Reference Centre for Ethics in the Life Sciences)
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
- Food and Drug Administration (FDA)
- CDER Drug and Biologic Approval Reports
- Pharmaceutical Research and Manufacturers of America (PhRMA)
- European Medicines Agency (EMEA)
- Pharmaceuticals and Medical Devices Agency (PMDA)
- WHO Model List of Essential Medicines
- Innovation and Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products - FDA
- Priority Medicines for Europe and the World Project "A Public Health Approach to Innovation" - WHO
- International Union of Basic and Clinical Pharmacology
- IUPHAR Committee on Receptor Nomenclature and Drug Classification