Pharmacoproteomics Applications for Drug Target Discovery in CNS Disorders

Although target-based approach has yielded novel drugs in many therapeutic fields, this approach remains suboptimal and slows the pace of innovations for drug discovery in central nervous system (CNS) disorders. This is because the target identification requires a hierarchical integration from in vitro cellular and functional tissue studies to animal models that reasonably predict drug effects in humans. Because the majority of CNS drugs were discovered empirically to date, the precise target site(s) for many of them remain unknown or uncertain, even after years of clinical and commercial use. This paper presents a critical review and synthesis of the emerging proteomics applications for drug target discovery with an emphasis on defining the early molecular mechanisms by which (hitherto empirically discovered) drugs or novel neurotrophic factors initiate cellular change toward physiological effects with therapeutic ramifications. Pharmacoproteomics methodology provides important qualitative information on post-translational modifications to each protein as well as quantitative data on protein expression patterns in response to a given pharmaceutical stimulus. This information is particularly important because it provides data on early cellular events such as the stimulus and signaling cascades triggered independently of protein neosynthesis. Pharmacoproteomics is still in its infancy but offers substantial promise in personalized medicine in addition to the pharmacogenomics methodologies.