Towards Structural Systems Pharmacology to Study Complex Diseases and Personalized Medicine

Abstract

Genome-Wide Association Studies (GWAS), whole genome sequencing, and high-throughput omics techniques have generated vast amounts of genotypic and molecular phenotypic data. However, these data have not yet been fully explored to improve the effectiveness and efficiency of drug discovery, which continues along a one-drug-one-target-one-disease paradigm. As a partial consequence, both the cost to launch a new drug and the attrition rate are increasing. Systems pharmacology and pharmacogenomics are emerging to exploit the available data and potentially reverse this trend, but, as we argue here, more is needed. To understand the impact of genetic, epigenetic, and environmental factors on drug action, we must study the structural energetics and dynamics of molecular interactions in the context of the whole human genome and interactome. Such an approach requires an integrative modeling framework for drug action that leverages advances in data-driven statistical modeling and mechanism-based multiscale modeling and transforms heterogeneous data from GWAS, high-throughput sequencing, structural genomics, functional genomics, and chemical genomics into unified knowledge. This is not a small task, but, as reviewed here, progress is being made towards the final goal of personalized medicines for the treatment of complex diseases.

Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network

“…The study of these secondary alterations might allow to understand the pathophysiology of these diseases, as well as to identify new biomarkers and therapeutic targets [15]. Nevertheless, to understand the effect of these secondary altered processes and to identify new biomarkers require to consider these diseases as a biological system, which are the product of the relation of multiple metabolic pathways, genes, proteins, and networks [16,17]. Impairment of metabolic normal states generate changes in concentrations of metabolites, consequence of disturbance of distribution of water in compartments or the high or low activity of enzymes that is altered by many mechanism [18,19].…”

Tryptophan Metabolites: A Microbial Perspective

“…Efforts have been directed to combine all into a unifi ed knowledge. Structural systems pharmacology framework is a drug discovery platform, which aims to be an integrative modelling framework for drug action (Xie et al 2014 ). Chang et al have recently used this approach to predict novel antimicrobial targets in Escherichia coli K12 MG1655 expanded genome-scale model (GEM-PRO) (Chang et al 2013 ;Monk et al 2013 ).…”

An Indian eye to personalized medicine

“…Ever since the HGP gained momentum and acceptance, it has been a "guiding star" to most of the drug design and pharmaceutical oriented companies [11]. Working in close reference and tandem with the genomic data, aids efficient and to-the-point analysis.…”