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Register a new userStructure and dynamics of molecular networks: A novel paradigm of drug discovery. A comprehensive review
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Despite considerable progress in genome- and proteome-based high-throughput screening methods and in rational drug design, the increase in approved drugs in the past decade did not match the increase of drug development costs. Network description and analysis not only give a systems-level understanding of drug action and disease complexity, but can also help to improve the efficiency of drug design. We give a comprehensive assessment of the analytical tools of network topology and dynamics. The state-of-the-art use of chemical similarity, protein structure, protein-protein interaction, signaling, genetic interaction and metabolic networks in the discovery of drug targets is summarized. We propose that network targeting follows two basic strategies. The central hit strategy selectively targets central nodes/edges of the flexible networks of infectious agents or cancer cells to kill them. The network influence strategy works against other diseases, where an efficient reconfiguration of rigid networks needs to be achieved by targeting the neighbors of central nodes or edges. It is shown how network techniques can help in the identification of single-target, edgetic, multi-target and allo-network drug target candidates. We review the recent boom in network methods helping hit identification, lead selection optimizing drug efficacy, as well as minimizing side-effects and drug toxicity. Successful network-based drug development strategies are shown through the examples of infections, cancer, metabolic diseases, neurodegenerative diseases and aging. Summarizing more than 1200 references we suggest an optimized protocol of network-aided drug development, and provide a list of systems-level hallmarks of drug quality. Finally, we highlight network-related drug development trends helping to achieve these hallmarks by a cohesive, global approach.
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During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into cumulus-type, i.e., those similar to puffy (white) clouds, and stratus-type, i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energy transmission processes. In the first class, there is limited overlap between the modules, which implies higher rigidity of the individual units; there the conformational changes can be described by an energy transfer mechanism. In the second class, the topology presents a compact structure with significant overlap between the modules; there the conformational changes can be described by multi-trajectories; that is, multiple highly populated pathways. We further propose that disordered protein regions evolved to help other protein segments reach rarely visited but functionally-related states. We also show the role of disorder in spatial games of amino acids; highlight the effects of intrinsically disordered proteins (IDPs) on cellular networks and list some possible studies linking protein disorder and protein structure networks.
The complexity of many biological, social and technological systems stems from the richness of the interactions among their units. Over the past decades, a great variety of complex systems has been successfully described as networks whose interacting pairs of nodes are connected by links. Yet, in face-to-face human communication, chemical reactions and ecological systems, interactions can occur in groups of three or more nodes and cannot be simply described just in terms of simple dyads. Until recently, little attention has been devoted to the higher-order architecture of real complex systems. However, a mounting body of evidence is showing that taking the higher-order structure of these systems into account can greatly enhance our modeling capacities and help us to understand and predict their emerging dynamical behaviors. Here, we present a complete overview of the emerging field of networks beyond pairwise interactions. We first discuss the methods to represent higher-order interactions and give a unified presentation of the different frameworks used to describe higher-order systems, highlighting the links between the existing concepts and representations. We review the measures designed to characterize the structure of these systems and the models proposed in the literature to generate synthetic structures, such as random and growing simplicial complexes, bipartite graphs and hypergraphs. We introduce and discuss the rapidly growing research on higher-order dynamical systems and on dynamical topology. We focus on novel emergent phenomena characterizing landmark dynamical processes, such as diffusion, spreading, synchronization and games, when extended beyond pairwise interactions. We elucidate the relations between higher-order topology and dynamical properties, and conclude with a summary of empirical applications, providing an outlook on current modeling and conceptual frontiers.
Genetic regulation is a key component in development, but a clear understanding of the structure and dynamics of genetic networks is not yet at hand. In this work we investigate these properties within an artificial genome model originally introduced by Reil. We analyze statistical properties of randomly generated genomes both on the sequence- and network level, and show that this model correctly predicts the frequency of genes in genomes as found in experimental data. Using an evolutionary algorithm based on stabilizing selection for a phenotype, we show that robustness against single base mutations, as well as against random changes in initial network states that mimic stochastic fluctuations in environmental conditions, can emerge in parallel. Evolved genomes exhibit characteristic patterns on both sequence and network level.
We consider the problem of inferring the probability distribution of flux configurations in metabolic network models from empirical flux data. For the simple case in which experimental averages are to be retrieved, data are described by a Boltzmann-like distribution ($propto e^{F/T}$) where $F$ is a linear combination of fluxes and the `temperature parameter $Tgeq 0$ allows for fluctuations. The zero-temperature limit corresponds to a Flux Balance Analysis scenario, where an objective function ($F$) is maximized. As a test, we have inverse modeled, by means of Boltzmann learning, the catabolic core of Escherichia coli in glucose-limited aerobic stationary growth conditions. Empirical means are best reproduced when $F$ is a simple combination of biomass production and glucose uptake and the temperature is finite, implying the presence of fluctuations. The scheme presented here has the potential to deliver new quantitative insight on cellular metabolism. Our implementation is however computationally intensive, and highlights the major role that effective algorithms to sample the high-dimensional solution space of metabolic networks can play in this field.
Metabolic networks are known to be scale free but the evolutionary origin of this structural property is not clearly understood. One way of studying the dynamical process is to compare the metabolic networks of species that have arisen at different points in evolution and hence are related to each other to varying extents. We have compared the reaction sets of each metabolite across and within 15 groups of species. For a given pair of species and a given metabolite, the number $Delta k$ of reactions of the metabolite that appear in the metabolic network of only one species and not the other is a measure of the distance between the two networks. While $Delta k$ is small within groups of related species and large across groups, we find its probability distribution to be $sim (Delta k)^{-gamma}$ where $gamma$ is a universal exponent that is the same within and across groups. This exponent equals, upto statistical uncertainties, the exponent $gamma$ in the scale free degree distribution $sim k^{-gamma}$. We argue that this, as well as our finding that $Delta k$ is approximately linearly correlated with the degree $k$ of the metabolite, is evidence of a `proportionate change process in evolution. We also discuss some molecular mechanisms that might be responsible for such an evolutionary process.
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