2.3 D RUG P ATENTS
3.1.1 Drug Discovery
A drug works by acting on a disease target and thus drug discovery include compound discovery and target discovery. Both discoveries starts
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with unknown goals or targets, and requires mainly scientific researchers to explore the potential drug candidates.
Based on the methods used in drug discovery, it can be categorized into two approaches, irrational and rational approaches.
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Irrational approach is a conventional method. A scientist scans compounds that are isolated from natural sources for a potential target that might have an effect on a certain assay. This approach requires scanning of thousands of compounds in order to find one that works. Scientist then researched on the underlyingmechanism of the target. The screening process is long and random and the failure risk is high.
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However, with the advancement of technology, scientists are now able to delineate the causal mechanism of a disease and identify a potential drug target. Then, scientist design a compound that would affect the target by interacting with the target. With the advanced knowledge and tools, current discovery usually employs the rational approach. The approach is typically divided into target identification, target validation, lead compound identification and lead optimization phase.Target Identification and Validation
A disease is a condition which alters or interferes with the normal state of an organism and is usually characterized by the abnormal functioning of one or more of the host's systems, parts or organs
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. Therefore, to understand the cause of a disease, scientist must elucidate the underlying mechanism and, if possible, identify the specific molecules that go wrong. Targetidentification is to identify the origin of a disease and the potential targets for intervention.
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There are several methods to identify potential targets but36
Rick Ng, Drugs: From Discovery to Approval 20 (2nd ed. 2009).
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Id.
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Raymond G. Hill, Humphrey P. Rang, Drug Discovery & Development 20 (2nd ed. 2013).
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F. Hoffmann-La Roche Ltd, Drawn to Science: Target identification in drug discovery,
http://www.roche.com/media/roche_stories/roche-stories-2013-09-11.htm (last visited Oct. 19, 2014).
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two are major types. The first approach starts with the understanding of the pathway causing the disease phenotype and to the selection of drug targets.
In other words, this approach starts with the study of patients who have the same phenotype, understanding the underlying cause of the disease of these people and then searching for the drug candidates. This approach involves analysis of the pathway that leads to disease first, and is therefore called backward approach.
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Another approach is so called forward approach. The forward approach starts by studying a certain signaling pathway andgenotype, changing the pathway, and see how the changed pathway affected the disease phenotype. This new approach becomes possible because of the highly developed DNA sequencing technology and human genome project.
With the understanding of the human genome and the ability to manipulate genes, scientists now can alter specific genes and create a specific genotype in a mouse model. By studying the phenotype of the specific genotype, scientists can delineate the relevant biological pathways and identify a potential drug target.
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Once the drug target is identified, researchers need to find direct
evidence that shows the validity of the potential target to be a successful drug target. Target validation is a series of experiments. In this phase, scientists are trying to understand the functions and importance of the target. In addition, validation studies can involve in vitro and/or in vivo tests. By in vitro studies, scientists evaluate and validate the target at molecular level while by in vivo studies, scientists can validate the target at biological and phenotypic level.
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In this phase, scientists also research on potential indicators that shows the effect of a drug to interact with the target and develop assays that are used to validate desirable interaction between a compound and the target.
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Supra note 38, at 65-67.
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Supra note 36, at 23.
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Supra note 36, at 28-30.
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Therefore, in target identification and target validation phases, there is generally still no drug compound actually involved in the research.
Lead Identification
Once the target is selected, scientists try to identify compounds that intervene with the selected target and molecular characteristics of the compounds are also evaluated at this phase. Several approaches are used to identify lead compounds, including existing drugs, natural ligands, natural products, focused screening, rational structure-based design,
knowledge-based design, fragment screening virtual screening,
high-throughput screening, etc.
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Among all, high-throughput screening is one of the most employed approaches to identify lead compound. It is conducted by experimenting on large numbers of compounds for their biological activity against the drug target. Identification of lead compounds can involve several tiers of screening. Primary screening provides initial positive and active compounds. These compounds are then tested in a secondary screening assays to confirm their activity and are studied for their potency and early specificity of the target.44
The compound hits filtered by secondary screening are studied for their structure-activity relationship and the target specificity. Structure-activity relationship (SAR) aim to study the chemical structure and its biological activity. With SAR information, a medicinal chemist would have a preliminary understanding of the amendability of the compounds and preliminary target specificity, and is capable of synthesizing a small group of compounds with structure similar to the compound hits. The pool of the compound hits and the small group derivatives are the leads identified.45
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Supra note 38, at 123.
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Supra note 38, at 97-98.
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Id.
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Advanced technology development has made the lead identification more productive and efficient. The technologies include X-ray
crystallography, nuclear magnetic resonance spectroscopy, computational chemistry, combinatorial chemistry and bioinformatics.
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These technologies either increase the pool of compound library, improve the quality of lead identification or help scientists better understand SAR.Lead Optimization
With SAR information and previous biological activity data, medicinal chemists can modify the compounds in order to improve properties that are required for pre-clinical development. The major required properties to screen the lead compounds and the modified compounds are selectivity, potency and absorption, distribution, metabolism and excretion (ADME) properties.
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Medicinal chemists provide modified lead compounds to biologist for biological property testing (mainly in vitro testing). Results of the biological testing are feedbacked to medicinal for further SAR evaluation and structural modification. The process keeps repeating until severaloptimized compounds are identified. Only a few optimized compounds enter
in vivo animal studies for further ADME evaluation. 48
In most cases,exploratory toxicity and safety profile are also studied at this phase.
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The final identified compounds would have good efficacy, safety and ADME profiles and are ready for pre-clinical studies. These identified compounds are the optimized lead compounds or called the drug candidates.Drug discovery starts from cultivating a therapeutic concept to generating drug candidates. This process takes a very long time to identify
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Supra note 36, at 60-71.
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Supra note 38, at 126.
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Supra note 36, at 58.
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Supra note 38, at 128-129.
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few promising but still risky drug candidates. It involves scientists in different fields to select an estimated 250 drug candidates out of 5000 to 10000 compounds.