Information about Drug Discovery
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.[1] However, data indicates that "new targets" as opposed to "established targets" are more prone to drug discovery project failure in general.[2] 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.
"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.
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:
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".
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.[1] However, data indicates that "new targets" as opposed to "established targets" are more prone to drug discovery project failure in general.[2] 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.
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
- Pharmacogenetics
- Molecular modelling
Notes
1. ^ this requires substantiation with one or more reputable sources from the time of enthusiasm following "completion" of the human genome sequence
2. ^ Drug Discovery & Development, October 2005, reporting on industry trends in 2003–2005''
2. ^ Drug Discovery & Development, October 2005, reporting on industry trends in 2003–2005''
References
- Shayne Cox Gad (2005), Drug Discovery Handbook, Wiley-Interscience, ISBN 0-471-21384-5
- 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
- QSAR World
- Molecular Conceptor
Topics in Medicinal Chemistry |
|---|
| ADME | Bioavailability | Chemogenomics | Drug Design | Drug Discovery | Enzyme Inhibition | Mechanism of Action | New Chemical Entity | Pharmacodynamics | Pharmacokinetics | Pharmacology | Pharmacophore | Quantitative Structure-Activity Relationship |
Medicine is the science and "" of maintaining and/or restoring human health through the study, diagnosis, and treatment of patients. The term is derived from the Latin ars medicina meaning the art of healing.
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Biotechnology is technology based on biology, especially when used in agriculture, food science, and medicine. The United Nations Convention on Biological Diversity has come up with one of many definitions of biotechnology:[1]
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- "
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Pharmacology is the study of how drugs interact with living organisms to produce a change in function.[1] If substances have medicinal properties, they are considered pharmaceuticals.
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A medication, medicine or drug is any substance or combination of substances administered to human beings or animals to treat or prevent disease; alternatively to assist in medical diagnosis.
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Serendipity is the effect by which one accidentally discovers something fortunate, especially while looking for something else entirely. The word derives from an old Persian fairy tale and was coined by Horace Walpole on 28 January 1754 in a letter he wrote to his friend Horace
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disease is an abnormal condition of an organism that impairs bodily functions. In human beings, "disease" is often used more broadly to refer to any condition that causes discomfort, dysfunction, distress, social problems, and/or death to the person afflicted, or similar problems
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An infection is the detrimental colonization of a host organism by a foreign species. In an infection, the infecting organism seeks to utilize the host's resources to multiply (usually at the expense of the host).
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Molecular biology is the study of biology at a molecular level. The field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry. Molecular biology chiefly concerns itself with understanding the interactions between the various systems of a cell,
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Physiology (from Greek: φυσις, physis, “nature, origin”; and λόγος, logos, "knowledge") is the study of the mechanical, physical, and biochemical functions of living organisms.
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Drug development or preclinical development is defined in many pharmaceutical companies as the process of taking a new chemical lead through the stages necessary to allow it to be tested in human clinical trials, although a broader definition would encompass the entire
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In health care, a clinical trial is a comparison test of a medication or other medical treatment (such as a medical device), versus a placebo (inactive look-a-like), other medications/devices, or the standard medical treatment for a patient's condition.
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human genome is the genome of Homo sapiens, which is composed of 24 distinct pairs of chromosomes (22 autosomal + X + Y) with a total of approximately 3 billion DNA base pairs containing an estimated 20,000–25,000 genes.
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In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an
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Proteins are large organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues.
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G protein-coupled receptors (GPCRs), also known as seven transmembrane receptors, 7TM receptors, heptahelical receptors, and G protein linked receptors (GPLR
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protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). This class of protein is further separated into subsets such as PKC alpha, PKC beta, and PKC gamma, each with specific functions.
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High-throughput screening (HTS), is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry.
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Purpose and method
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receptor antagonist is a drug that does not provoke a biological response itself upon binding to a receptor, but blocks or attenuates agonist-mediated responses. It may be competitive (or surmountable), i.e.
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agonist is a substance that binds to a specific receptor and triggers a response in the cell. It mimics the action of an endogenous ligand (such as hormone or neurotransmitter) that binds to the same receptor.
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protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). This class of protein is further separated into subsets such as PKC alpha, PKC beta, and PKC gamma, each with specific functions.
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Enzyme inhibitors are molecules that bind to enzymes and decrease their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides.
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Toxicity is the degree to which something is able to produce illness or damage to an exposed organism. Toxicity can refer to the effect on a whole organism, such as a human or a bacterium or a plant, or to a substructure, such as a cell (cytotoxicity) or an organ (organotoxicity
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Pharmacological or biological activity is an expression describing the beneficial or adverse effects of a drug on living matter. When the drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or pharmacophore but can be modified by
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A pharmacophore was first defined by Paul Ehrlich in 1909 as "a molecular framework that carries (phoros) the essential features responsible for a drug’s (=pharmacon's) biological activity" (Ehrlich. Dtsch. Chem. Ges. 1909, 42: p.17).
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Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacology involved with designing, synthesizing and developing pharmaceutical drugs.
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Structure-activity relationship is the traditional Practices of Medicinal chemistry which try to modify the effect or the potency of Bioactive chemical compound by modifying its Chemical structure.
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A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.
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ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism.
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In vitro (Latin: (with) in the glass) refers to the technique of performing a given experiment in a test tube, or, generally, in a controlled environment outside a living organism. In vitro fertilization is a well-known example of this.
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In vivo (Latin: (with)in the living) means that which takes place inside an organism. In science, in vivo refers to experimentation done in or on the living tissue of a whole, living organism as opposed to a partial or dead one.
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