Abstract
In this paper, we propose DeCoST (Drug Repurposing from Control System Theory) framework to apply control system paradigm for drug repurposing purpose. Drug repurposing has become one of the most active areas in pharmacology since the last decade. Compared to traditional drug development, drug repurposing may provide more systematic and significantly less expensive approaches in discovering new treatments for complex diseases. Although drug repurposing techniques rapidly evolve from “one: disease-gene-drug” to “multi: gene, dru” and from “lazy guilt-by-association” to “systematic model-based pattern matching,” mathematical system and control paradigm has not been widely applied to model the system biology connectivity among drugs, genes, and diseases. In this paradigm, our DeCoST framework, which is among the earliest approaches in drug repurposing with control theory paradigm, applies biological and pharmaceutical knowledge to quantify rich connective data sources among drugs, genes, and diseases to construct disease-specific mathematical model. We use linear–quadratic regulator control technique to assess the therapeutic effect of a drug in disease-specific treatment. DeCoST framework could classify between FDA-approved drugs and rejected/withdrawn drug, which is the foundation to apply DeCoST in recommending potentially new treatment. Applying DeCoST in Breast Cancer and Bladder Cancer, we reprofiled 8 promising candidate drugs for Breast Cancer ER+ (Erbitux, Flutamide, etc.), 2 drugs for Breast Cancer ER- (Daunorubicin and Donepezil) and 10 drugs for Bladder Cancer repurposing (Zafirlukast, Tenofovir, etc.).
Highlights
Drug repurposing has become one of the most active areas in pharmacology since last decade (Oprea et al, 2011) because this approach could significantly reduce the cost and time to invent a new treatment
From good performance when classifying between approved drugs and withdrawn drugs, we find 7 compounds that may be promising in Breast Cancer ER-positive subtype, 3 compounds in Breast Cancer ER-negative subtype and 10 compounds in Bladder Cancer for further drug repurposing in-vivo study
On the drugs covered in Connectivity Maps (CMAP), DeCoST achieves area under the curve (AUC) of 0.91, which is much higher than the AUC achieved by CMAP (0.79), as showed in the Supplemental Text 1
Summary
Drug repurposing ( called drug repositioning) has become one of the most active areas in pharmacology since last decade (Oprea et al, 2011) because this approach could significantly reduce the cost and time to invent a new treatment. Drug repurposing finds new indications for known drugs and compounds (Gupta et al, 2013) to reduce the risk of failure and shorten time of discovery. Drug repurposing applies modern computational techniques to digitalize genomic (Power et al, 2014), bioinformatics, chemical informatics (Bisson, 2012) and patients’ individual health records (Xu et al, 2014) to offer more systematic evaluation of the chemical compound before entering the laboratory testing and clinical trial steps. Prominent successful examples for drug repurposing include Viagra, Avastin, and Rituxan (Dudley et al, 2011)
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