Background of Central Nervous System (CNS) Drug Discovery
The need for novel therapies for CNS disorders with improved efficacy, safety, and tolerability has never been in question, as it is widely recognized that, even with currently utilized treatments, CNS disorders are major contributors to the global burden of illness and incur high economic costs. Unfortunately, over the past two decades, with a few exceptions, CNS drug discovery has been relatively unsuccessful in delivering new drugs for psychiatric and neurological disorders. Although many technical issues associated with developing drugs for CNS disorders have been addressed, the core of the problem lies in the identification and validation of novel drug targets for these disorders.
Target Identification
Target identification is the process to identify the direct molecular target (such as protein or nucleic acid) of a small molecule. It is aimed at finding the efficacy target of a drug. The techniques applied may be based on principles of biochemistry, genetics, chemical biology, biophysics, or other disciplines. For instance, there are three distinct and complementary approaches for discovering the protein target of a small molecule, including direct biochemical methods, genetic interaction methods, and computational inference methods. The postulated mechanisms for new compounds emerge from such tests. The target pathway is inferred but remains to be confirmed. In fact, many target identification projects proceed through a combination of these methods, where researchers employ both direct measurements and inferences to test specific target hypotheses.
-
Direct biochemical methods
Direct biochemical methods involve labeling the protein or small molecule of interest, incubation of the two populations, and direct detection of binding. Biochemical affinity purification provides the most direct approach to finding target proteins that bind small molecules of interest. Moreover, affinity chromatography has been coupled with powerful new techniques in mass spectrum (MS), which can provide the most sensitive and unbiased methods of finding target proteins.
-
Genetic interaction methods
Genetic interaction methods can also be used to identify protein targets by modulating presumed targets in cells, thereby changing small-molecule sensitivity. Target identification based on genetic or genomic methods leverages the relative ease of working with DNA and RNA to perform large-scale modifications and measurements. These methods often use the principle of genetic interaction, relying on the idea of genetic modifiers to generate target hypotheses.
-
Computational inference methods
Using pattern recognition to compare small-molecule effects to those of known reference molecules, target hypotheses can be generated by computational inference
Target Validation
One of the greatest challenges we face in CNS drug discovery is in target validation. CNS diseases are extremely heterogeneous, difficult to diagnose, and in many cases, have a poorly understood etiology and pathology. To be able to accurately select the right target as a key mechanism for a disease state, a greater understanding of the molecular basis of CNS diseases is needed. Often, the difficulty at this stage is the lack of a selective small-molecule tool, the quality, and selectivity of which may influence the outcome. If the tool molecule is not fully selective, it may feasibly cause off-target effects that could be mistaken for mechanism-based side effect liabilities. In the absence of a small-molecule tool, a neutralizing antibody, small interfering ribonucleic acid, or genetically modified animals may be used as tools for validation purposes.
Animal models currently play a central role in the target validation process and subsequently in the development of preclinical candidates in most areas of pharmaceutical research, including CNS disorders. Since many CNS disorders are found naturally only in humans, the term animal model, as it relates to such disorders, is somewhat of a misnomer. Therefore, three criteria including construct validity, face validity and predictive validity have been proposed.
Target identification and validation is a process to accumulate the evidence for and against a target, and typically, 12-18 months are taken to conducting new research or replicating literature studies to build sufficient evidence. Equipped with extensive experience, profound expertise and state-of-the-art instruments, Creative Biolabs offers one-stop services of target identification and validation for CNS drug development, particularly psychotropic drug development. Please contact us for more information and a detailed quote.
For Research Use Only.
