Applying systems biology in drug discovery and development

Abstract

Translational research is a continuum between clinical and basic research where the patient is the center of the research process. It brings clinical research to a starting point for the drug discovery process, permitting the generation of a more robust pathophysiological hypothesis essential for a better selection of drug targets and candidate optimization. It also establishes the basis of early proof for clinical concept studies, preferably in phase I, for which biomarkers and surrogate endpoints can often be used. Systems biology is a prerequisite approach to translational research where technologies and expertise are integrated and articulated to support efficient and productive realization of this concept. The first component of systems biology relies on omics-based technologies and integrates the changes in variables, such as genes, proteins and metabolites, into networks that are responsible for an organism's normal and diseased state. The second component of systems biology is in the domain of computational methods, where simulation and modeling create hypotheses of signaling pathways, transcription networks, physiological processes or even cell- or organism-based models. The simulations aim to show the origin of perturbations of the system that lead to pathological states and what treatment could be achieved to ameliorate or normalize the system. This review discusses how translational research and systems biology together could improve global understanding of drug targets, suggest new targets and approaches for therapeutics, and provide a deeper understanding of drug effects. Taken together, these types of analyses can lead to new therapeutic options while improving the safety and efficacy of new and existing medications.

Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders

“…In recent years, mirroring interest in neural circuits, "Network Pharmacology" and "Systems biology" (Galizzi et al, 2013;Kotaleski and Blackwell, 2010;Mei et al, 2012;Nussinov et al, 2011;Phillips et al, 2012;Silverman and Loscalzo, 2012), there has been a move towards phenotypic screening. That is, studies of biological actions performed in integrated systems rather than on single cells/proteins, and using a diversity of functional readouts from cellular signalling to neuritic outgrowth to synaptic transmission to (in vivo) behaviour (Lee et al, 2011;Penrod et al, 2011;SamsDodd, 2013;Swinney, 2014;Swinney and Anthony, 2011;Winchester et al, 2014).…”

“…Hence, while HTS programmes tend to ignore and eliminate any interaction other than the one targeted, phenotypic strategies are more likely to detect and pursue agents with unexpected actions and/or multi-modal profiles (Section 7.1) (Galizzi et al, 2013;Hasan et al, 2012;Mei et al, 2012).…”

The Application of Omics Technologies to the Study of Mammalian Toxicology

“…Expression changes of genes, proteins and metabolites are organized into networks where computation modeling allows simulation and modeling to create hypotheses of signaling pathways, transcription networks, physiological processes or even cell-or organism-based models [100]. The goal of such efforts is to allow for a detailed modeling of biological processes at the molecular level and their relationship to macroscopic observations of toxicity, and to identify critical steps in a toxicological process.…”

Gene expression profiling of immunomagnetically separated cells directly from stabilized whole blood for multicenter clinical trials

“…There is an ever-increasing demand for the discovery, validation, and application of clinically useful molecular biomarkers that enable patient stratification, diagnosis, monitoring of disease progression, or a better understanding of drug response (safety and efficacy) [1][2][3]. Gene expression biomarkers have been investigated in various diseases such as autoimmune diseases [4,5], cancer [6][7][8], neurological diseases [9,10], infections [11,12] and in transplantation [13,14].…”