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Title: Towards systems pharmacology models of druggable targets and disease mechanisms
Author: Knight-Schrijver, Vincent
ISNI:       0000 0004 7651 2854
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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The development of essential medicines is being slowed by a lack of efficiency in drug development as ninety per cent of drugs fail at some stage during clinical evaluation. This attrition in drug development is seen not because of a reduction in pharmaceutical research expenditure nor is it caused by a declining understanding of biology, if anything, these are both increasing. Instead, drugs are failing because we are unable to effectively predict how they will work before they are given to patients. This is due to limitations of the current methods used to evaluate a drug's toxicity and efficacy prior to its development. Quite simply, these methods do not account for the full complexity of biology in humans. Systems pharmacology models are a likely candidate for increasing the efficiency of drug discovery as they seek to comprehensively model the fundamental biology of disease mechanisms in a quantit- ative manner. They are computational models, designed and hailed as a strategy for making well-informed and cost effective decisions on drug viability and target druggability and therefore attempt to reduce this time-consuming and costly attrition. Using text mining and text classification I present a growing landscape of systems pharmacology models in literature growing from humble roots because of step-wise increases in our understanding of biology. Furthermore, I develop a case for the capability of systems pharmacology models in making predictions by constructing a model of interleukin-6 signalling for rheumatoid arthritis. This model shows that druggable target selection is not necessarily an intuitive task as it results in an emergent but unanswered hypothesis for safety concerns in a monoclonal antibody. Finally, I show that predictive classification models can also be used to explore gene expression data in a novel work flow by attempting to predict patient response classes to an influenza vaccine.
Supervisor: Le Novère, Nicolas Sponsor: BBSRC ; GlaxoSmithKline
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Systems Pharmacology ; Text Mining ; Quantitative Systems Pharmacology ; Drug Discovery ; Computational Modelling ; Interleukin-6 ; Rheumatoid Arthritis ; Drug Development ; Bioinformatics ; Classification ; Systems Biology