System‐based strategies for p53 recovery. Issue 3 (15th January 2018)

• Record Type: Journal Article
• Authors: Azam, Muhammad Rizwan; Fazal, Sahar; Ullah, Mukhtar; Bhatti, Aamer I.
• Is Part Of: IET systems biology. Volume 12:Issue 3(2018)
• Page Start: 101
• Page End: 107
• Publication Date: 2018-01-15
• Subjects: proteins -- tumours -- cancer -- cellular biophysics -- molecular biophysics -- molecular configurations -- biochemistry -- differential equations -- closed loop systems -- bifurcation -- biology computing; system‐based strategies -- p53 recovery -- systems theory‐based novel drug design approach -- dynamic system -- ordinary differential equations‐based mathematical model -- control engineering practices -- subsequent controller design -- wild‐type p53 -- p53 revival -- oscillatory -- control system paradigm -- mathematical model -- Nutlin effect -- attractor point analysis -- domain‐of‐attraction -- two‐loop negative feedback control strategy -- cellular concentration -- pharmacokinetic effects -- cancerous cells -- bifurcation analysis -- p53 oscillation -- anomalous cell; Systems biology -- Periodicals; Cell physiology -- Periodicals; Biological systems -- Mathematical models -- Periodicals; Genetics -- Mathematical models -- Periodicals; Computational biology -- Periodicals; 573
• DOI: 10.1049/iet-syb.2017.0025
• Languages: English
• ISSNs: 1751-8849

Abstract

Abstract : The authors have proposed a systems theory‐based novel drug design approach for the p53 pathway. The pathway is taken as a dynamic system represented by ordinary differential equations‐based mathematical model. Using control engineering practices, the system analysis and subsequent controller design is performed for the re‐activation of wild‐type p53. p53 revival is discussed for both modes of operation, i.e. the sustained and oscillatory. To define the problem in control system paradigm, modification in the existing mathematical model is performed to incorporate the effect of Nutlin. Attractor point analysis is carried out to select the suitable domain of attraction. A two‐loop negative feedback control strategy is devised to drag the system trajectories to the attractor point and to regulate cellular concentration of Nutlin, respectively. An integrated framework is constituted to incorporate the pharmacokinetic effects of Nutlin in the cancerous cells. Bifurcation analysis is also performed on the p53 model to see the conditions for p53 oscillation.