Network-Based Tools for the Identification of Novel Drug TargetsAdapted from the opening presentation at the International Conference on Systems Biology of Human Disease (SBHD) in Boston, Massachusetts, 16 to 18 June 2010.

Abstract

In the past few years, network-based tools have become increasingly important in the identification of novel molecular targets for drug development. Systems-based approaches to predict signal transduction-related drug targets have developed into an especially promising field. Here, we summarize our studies, which indicate that modular bridges and overlaps of protein-protein interaction and signaling networks may be of key importance in future drug design. Intermodular nodes are very efficient in mediating the transmission of perturbations between signaling modules and are important in network cooperation. The analysis of stress-induced rearrangements of the yeast interactome by the ModuLand modularization algorithm indicated that components of modular overlap are key players in cellular adaptation to stress. Signaling crosstalk was much more pronounced in humans than in Caenorhabditis elegans or Drosophila melanogaster in the SignaLink (http://www.SignaLink.org) database, a uniformly curated database of eight major signaling pathways. We also showed that signaling proteins that participate in multiple pathways included multiple established drug targets and drug target candidates. Lastly, we caution that the pervasive overlap of cellular network modules implies that wider use of multitarget drugs to partially inhibit multiple individual proteins will be necessary to modify specific cellular functions, because targeting single proteins for complete disruption usually affects multiple cellular functions with little specificity for a particular process. Tools for analyzing network topology and especially network dynamics have great potential to identify alternative sets of targets for developing multitarget drugs.

Diverse array-designed modes of combination therapies in Fangjiomics

“…With the network influence strategy, breaking down the system's robustness to push the system from one that favors the diseased state to one that favors a healthy state is a difficult task. The preferred targets of the network influence strategy are considered as the connected nodes located in vulnerable points of disease-related networks such as in intermodular, bridging positions [60][61][62][63][64][65] . In signaling networks, the strategy of influencing preferred nodes in the network inhibits certain outputs of the signaling network, while leaving others intact to redirect the signal flow in the network [66][67][68] .…”

System Level Mechanisms of Adaptation, Learning, Memory Formation and Evolvability: The Role of Chaperone and Other Networks

“…Recent advances in network-related methodology identified several novel, complex centrality measures based on nonlocal network topology (see [77] and references therein). Recently network centrality measures based on perturbation propagation or influencing system-level cooperation have also been introduced [128]. As another recent development, driver nodes were defined making directed networks controllable [129], and other approaches finding key edges and nodes of network control also became available [130,131].…”

Nonlinear Response Amplification Mechanisms for Low Doses of Natural Product Nanomedicines: Dynamical Interactions with the Recipient Complex Adaptive System

“…Complexity in the nonlinear dynamics and functional organization of an intact cell or organism involves multiple interdependent and interactive functional relationships that can lead to indirect effects throughout the larger system [68,69,93,94]. The magnitude of those effects is nonlinear, i.e., it can be disportionately larger than the magnitude of the original stimulus [62][63][64].…”

“…As a result, nano-drugs and natural products can elicit changes in cells and distant parts of an organism not obvious from a bulk medicine focus on only local inhibitory effects for specific symptoms [69]. These concepts imply the importance of the salience of an NP as a potential danger signal, or therapeutic stimulus, for the organism as a whole, especially at low doses [21,92].Complexity in the nonlinear dynamics and functional organization of an intact cell or organism involves multiple interdependent and interactive functional relationships that can lead to indirect effects throughout the larger system [68,69,93,94]. The magnitude of those effects is nonlinear, i.e., it can be disportionately larger than the magnitude of the original stimulus [62][63][64].…”