The role of modelling in identifying drug targets for diseases of the cell cycle

Robert G. Clyde, James L. Bown, Ted R. Hupp, Nikolai Zhelev, John W. Crawford

Research output: Contribution to journalArticle

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Abstract

The cell cycle is implicated in diseases that are the leading cause of mortality and morbidity in the developed world. Until recently, the search for drug targets has focused on relatively small parts of the regulatory network under the assumption that key events can be controlled by targeting single pathways. This is valid provided the impact of couplings to the wider scale context of the network can be ignored. The resulting depth of study has revealed many new insights; however, these have been won at the expense of breadth and a proper understanding of the consequences of links between the different parts of the network. Since it is now becoming clear that these early assumptions may not hold and successful treatments are likely to employ drugs that simultaneously target a number of different sites in the regulatory network, it is timely to redress this imbalance. However, the substantial increase in complexity presents new challenges and necessitates parallel theoretical and experimental approaches. We review the current status of theoretical models for the cell cycle in light of these new challenges. Many of the existing approaches are not sufficiently comprehensive to simultaneously incorporate the required extent of couplings. Where more appropriate levels of complexity are incorporated, the models are difficult to link directly to currently available data. Further progress requires a better integration of experiment and theory. New kinds of data are required that are quantitative, have a higher temporal resolution and that allow simultaneous quantitative comparison of the concentration of larger numbers of different proteins. More comprehensive models are required and must accommodate not only substantial uncertainties in the structure and kinetic parameters of the networks, but also high levels of ignorance. The most recent results relating network complexity to robustness of the dynamics provide clues that suggest progress is possible.
Original languageEnglish
Pages (from-to)617-627
Number of pages11
JournalJournal of the Royal Society Interface
Volume3
Issue number10
DOIs
StatePublished - Oct 2006

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Anthralin
Castration
Cell Cycle
Cells
Supravalvular Aortic Stenosis
Uncertainty
Morbidity
Mortality
Proteins
Lutheran Blood-Group System
Common Bile Duct Diseases
Spontaneous Fractures
Kinetic parameters
Experiments

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Clyde, Robert G.; Bown, James L.; Hupp, Ted R.; Zhelev, Nikolai; Crawford, John W. / The role of modelling in identifying drug targets for diseases of the cell cycle.

In: Journal of the Royal Society Interface, Vol. 3, No. 10, 10.2006, p. 617-627.

Research output: Contribution to journalArticle

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The role of modelling in identifying drug targets for diseases of the cell cycle. / Clyde, Robert G.; Bown, James L.; Hupp, Ted R.; Zhelev, Nikolai; Crawford, John W.

In: Journal of the Royal Society Interface, Vol. 3, No. 10, 10.2006, p. 617-627.

Research output: Contribution to journalArticle

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