Drug Discov Ther 2007;1(1):23-29. Review Target validation: A door to drug discovery Xiu-Ping Chen, Guan-Hua Du* Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. ABSTRACT: From ancient times to today, a target is. The exact connotation of the term “drug drug discovery transitioned from serendipity to target” needs to be elucidated. Target validation is the rationality over its long history. Proper drug target first step in completely new drug discovery. Validation selection and validation are crucial to the discovery of new drug targets is the process of physiologically, of new drugs. This review discusses the definition pathologically, and pharmacologically evaluating a of drug targets and proposes several characteristics biomolecule and might be performed at the molecular, for drug targets. The limitations of the term ‘target’ cellular, or whole animal level. itself are summarized. The drug target validation Lectin-like oxidized low-density lipoprotein process is also discussed in detail and pitfalls during receptor-1 (LOX-1) was identified as a special receptor this process are outlined. Small active chemical for oxidized low-density lipoprotein (ox-LDL) in compounds obtained from the target validation endothelial cells (1). Accumulated studies revealed that process are useful tools in target validation and LOX-1 might play an important role in the pathogenesis target function research. The validation of lectin-like of atherosclerosis (2-7). Review of ten years of studies oxidized low-density lipoprotein receptor-1 (LOX-1) on LOX-1 suggested that LOX-1 might be a specific as a new potential anti-atherosclerotic drug target is new drug target, and validation results here revealed cited as an example in order to elucidate the target that LOX-1 is a new promising anti-atherosclerotic validation process. drug target. Key Words: Drug discovery, drug target, drug target Drug discovery: From serendipity to rationality validation, high-throughput screening, lectin-like oxidized low-density lipoprotein receptor-1 Drug discovery is one of the most crucial components of the pharmaceutical industry’s Research and Development (R&D) process and is the essential step in the generation of any robust, innovative drug pipeline. Introduction However, new drug discovery is an expensive, time- consuming, and difficult process. Moreover, the end In medicine, biotechnology, and pharmacology, drug result is never guaranteed. A single new drug can cost 1.2 discovery is generally thought of as the discovery, billion euros and take 10 years to develop (8). creation, or design of a compound or a complex that The early history of drug discovery is all about possesses the potential to become a useful therapeutic. natural products and herbal remedies, the use of which It is really an expensive, time-consuming, and difficult dates back thousands of years. In ancient times, drug process that involves the identification of candidates discovery was mainly based on the accumulation of and synthesis, characterization, screening, and assays experience from generation to generation. It is a rather of their therapeutic efficacy. The word ‘target’ has long process that involves huge costs in both money been widely used in both medical and pharmaceutical and even lives. Just like the discovery of penicillin, research. However, the definition of “target” itself is serendipity has been the key to the pharmaceutical vague and is debated within the pharmaceutical industry. industry’s success over many decades. Now with The number of drug targets is also controversial, due the development of modern chemistry, hundreds and in large degree to disputes over the definition of what sometimes thousands of chemical compounds have to be made and tested in an effort to find one that can achieve a desirable result. Thus, traditional drug *Correspondence to: Guan-Hua Du, Institute of Materia discovery strategy based on experience and serendipity Medica, Chinese Academy of Medical Sciences and is no longer able to meet the needs of pharmaceutical Peking Union Medical College, Beijing 100050, China; companies. A shift from serendipity to rationality in e-mail: [email protected] drug discovery is underway (Figure 1). Rational drug Received June 29, 2007 discovery based on knowledge of the biological system Accepted July 6, 2007 being investigated allows highly specific selective http://www.ddtjournal.com 23 Review Drug Discov Ther 2007;1(1):23-29. Figure 1. Drug discovery: From ‘Tasting to Testing.’ The emergence of an “accidental” approach to drug discovery has its origins in early history with traditional natural herbal remedies that were passed from generation to generation in local communities or tribes. The ancient Chinese legend that “Shen Nong tastes a hundred herbs in a single day and meets seventy toxins” demonstrates the great sufferings of our ancestors encountered during the discovery of new drugs. This experience- based drug discovery mode lasted for several thousands years. It was not until the late 18th and early 19th centuries that the active components of medicinal plants and herbal remedies were analyzed, resulting in the discovery of alkaloids. HTS and ultra-HTS developed during the later 1980s represent a new mode of drug discovery. These methods represent a multifunctional, multiskilled environment that connects a range of discovery functions in a high-capacity, integrated process producing a product that consists of a cohort of tractable chemical leads with respect to targets of interest. antagonists and agonists to be developed. These target is a key molecule involved in a particular molecules can then be developed as lead compounds, metabolic or signal transduction pathway that is specific drug candidates, and even drugs. to a disease condition or a specific disease. However, the term ‘drug target’ itself has several limitations and What are drug targets? is debated within the pharmaceutical industry. In this respect, several points should be kept in mind. Target identification and validation are the first key First, a drug target is a relative concept. For starters, stages in the drug discovery pipeline (9). But what a drug target is, just like other biomolecules, also a is a drug target? Generally speaking, a drug target biomolecule involved in a transduction pathway. The is the specific binding site of a drug in vivo through difference between the two is only in their location and which the drug exerts its action. A specific drug target role in the transduction pathway. Another aspect is that might have the following characteristics: 1) The a drug target is disease-dependent, that is, every target drug target is a biomolecule(s), normally a protein is involved in a special spectrum of diseases. that could exist in isolated or complex modality. 2) Second, most human diseases are rather complicated The biomolecules have special sites that match other and involve many risk factors, so there are clearly many molecules (commonly small molecules with special different drug targets with respect to a specific disease. structures). These molecules could be endogenous or Targeting a specific target could not conceivably cure extraneous substances such as chemical molecules a kind of disease. However, the involvement of many (drugs). 3) The biomolecular structure might change targets in a disease does not mean that each target shares when the biomolecule binds to small molecules and equally in the pathogenesis of the disease and thus drugs the changes in structure normally are reversible. 4) targeting these targets would not be equally effective in Following the change in the biomolecule’s structure the therapy of the disease. various physiological responses occur and induce Third, drug targets can change, which means that regulation of the cell, organ, tissue, or body status. 5) with the development of insights into biomolecules and The physiological responses triggered by the changes their role in the pathogenesis of a certain disease, drug in biomolecule structure play a major role in complex targets might be not as important as or may be much regulation and have a therapeutic effect on pathological more important than currently believed. In fact, the conditions. 6) The expression, activity, and structure of establishment of drug targets is based on understanding the biomolecule might change over the duration of the of the pathogenesis of the disease. pathological process. 7) Small molecules binding to the Fourth, there are many drugs targeting the same biomolecules are drugs (10). target and one drug may have more than one target. The As is apparent from the above discussion, a drug relationship between a drug and its target is not one-to- 24 http://www.ddtjournal.com Drug Discov Ther 2007;1(1):23-29. Review one but one-to-many or many-to-one. publication of draft maps of the human genome and an Fifth, when a new drug target is discovered and interim agreement that the human genome consists of validated, researchers usually hope to obtain more approximately 21,000 genes, there has been considerable specific drugs targeting the target. However, a key anticipation that many novel disease-specific molecular understanding to keep in mind is that the body is targets will be rapidly identified and that these will form a subtle organism and a more specific drug might the basis of many new drug discovery programs (13). disrupt the homeostasis of the body. Compared to According to the current definition, one could rationally aspirin, rofecoxib is a specific COX-2 inhibitor. predict that there are 5,000 to 10,000 established and However, studies had shown that rofecoxib increases potential drug targets in humans (10). cardiovascular risks, resulting in rofecoxib’s withdrawal from the drug market. Target validation Sixth, a drug target usually refers to a single biomolecule. This connotation should be revised. New target validation is the basis of completely new Recent research has noted that a complex, like HDL, for drug exploration and the initial step of drug discovery.