284 research outputs found
The efficiency of multi-target drugs: the network approach might help drug design
Despite considerable progress in genome- and proteome-based high-throughput
screening methods and rational drug design, the number of successful single
target drugs did not increase appreciably during the past decade. Network
models suggest that partial inhibition of a surprisingly small number of
targets can be more efficient than the complete inhibition of a single target.
This and the success stories of multi-target drugs and combinatorial therapies
led us to suggest that systematic drug design strategies should be directed
against multiple targets. We propose that the final effect of partial, but
multiple drug actions might often surpass that of complete drug action at a
single target. The future success of this novel drug design paradigm will
depend not only on a new generation of computer models to identify the correct
multiple hits and their multi-fitting, low-affinity drug candidates but also on
more efficient in vivo testing.Comment: 6 pages, 2 figures, 1 box, 38 reference
Creative elements: network-based predictions of active centres in proteins, cellular and social networks
Active centres and hot spots of proteins have a paramount importance in
enzyme action, protein complex formation and drug design. Recently a number of
publications successfully applied the analysis of residue networks to predict
active centres in proteins. Most real-world networks show a number of
properties, such as small-worldness or scale-free degree distribution, which
are rather general features of networks, from molecules to society at large.
Using analogy I propose that existing findings and methodology already enable
us to detect active centres in cells, and can be expanded to social networks
and ecosystems. Members of these active centres are termed here as creative
elements of their respective networks, which may help them to survive
unprecedented, novel challenges, and play a key role in the development,
survival and evolvability of complex systems.Comment: This contribution extends the content of a Nature Journal Club paper
(Nature 454:5) having 10 pages, 1 Figure and 50 references. It is the cover
story of the 2008 December Trends in Biochemical Sciences issu
Drug-therapy networks and the predictions of novel drug targets
Recently, a number of drug-therapy, disease, drug, and drug-target networks
have been introduced. Here we suggest novel methods for network-based
prediction of novel drug targets and for improvement of drug efficiency by
analysing the effects of drugs on the robustness of cellular networks.Comment: This is an extended version of the Journal of Biology paper
containing 2 Figures, 1 Table and 44 reference
Water and molecular chaperones act as weak links of protein folding networks: energy landscape and punctuated equilibrium changes point towards a game theory of proteins
Water molecules and molecular chaperones efficiently help the protein folding
process. Here we describe their action in the context of the energy and
topological networks of proteins. In energy terms water and chaperones were
suggested to decrease the activation energy between various local energy minima
smoothing the energy landscape, rescuing misfolded proteins from conformational
traps and stabilizing their native structure. In kinetic terms water and
chaperones may make the punctuated equilibrium of conformational changes less
punctuated and help protein relaxation. Finally, water and chaperones may help
the convergence of multiple energy landscapes during protein-macromolecule
interactions. We also discuss the possibility of the introduction of protein
games to narrow the multitude of the energy landscapes when a protein binds to
another macromolecule. Both water and chaperones provide a diffuse set of
rapidly fluctuating weak links (low affinity and low probability interactions),
which allow the generalization of all these statements to a multitude of
networks.Comment: 9 pages, 1 figur
Detecting Important Nodes to Community Structure Using the Spectrum of the Graph
Many complex systems can be represented as networks, and how a network breaks
up into subnetworks or communities is of wide interest. However, the
development of a method to detect nodes important to communities that is both
fast and accurate is a very challenging and open problem. In this manuscript,
we introduce a new approach to characterize the node importance to communities.
First, a centrality metric is proposed to measure the importance of network
nodes to community structure using the spectrum of the adjacency matrix. We
define the node importance to communities as the relative change in the
eigenvalues of the network adjacency matrix upon their removal. Second, we also
propose an index to distinguish two kinds of important nodes in communities,
i.e., "community core" and "bridge". Our indices are only relied on the
spectrum of the graph matrix. They are applied in many artificial networks as
well as many real-world networks. This new methodology gives us a basic
approach to solve this challenging problem and provides a realistic result.Comment: 10 pages,7 gigure
Ageing as a price of cooperation and complexity: Self-organization of complex systems causes the ageing of constituent networks
The analysis of network topology and dynamics is increasingly used for the description of the structure, function and evolution of complex systems. Here we summarize key aspects of the evolvability and robustness of the hierarchical network-set of macromolecules, cells, organisms, and ecosystems. Listing the costs and benefits of cooperation as a necessary behaviour to build this network hierarchy, we outline the major hypothesis of the paper: the emergence of hierarchical complexity needs cooperation leading to the ageing of the constituent networks. Local cooperation in a stable environment may lead to over-optimization developing an ‘always-old’ network, which ages slowly, and dies in an apoptosis-like process. Global cooperation by exploring a rapidly changing environment may cause an occasional over-perturbation exhausting system-resources, causing rapid degradation, ageing and death of an otherwise ‘forever-young’ network in a necrosis-like process. Giving a number of examples we explain how local and global cooperation can both evoke and help successful ageing. Finally, we show how various forms of cooperation and consequent ageing emerge as key elements in all major steps of evolution from the formation of protocells to the establishment of the globalized, modern human society. Thus, ageing emerges as a price of complexity, which is going hand-in-hand with cooperation enhancing each other in a successful community
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