Towards structural systems pharmacology to study complex diseases and personalized medicine.
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.
Department of Computer Science, Hunter College, The City University of New York, New York, New York, United States of America; Ph.D. Program in Computer Science, Biology, and Biochemistry, The Graduate Center, The City University of New York, New York, New York, United States of America.
Lei
L
Xie
Department of Computer Science, Hunter College, The City University of New York, New York, New York, United States of America.
Xiaoxia
X
Ge
Department of Computer Science, Hunter College, The City University of New York, New York, New York, United States of America.
Hepan
H
Tan
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.
Li
L
Xie
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.
Yinliang
Y
Zhang
Department of Biological Sciences, Hunter College, The City University of New York, New York, New York, United States of America.
Thomas
T
Hart
School of Public Health, Hunter College, The City University of New York, New York, New York, United States of America.
Xiaowei
X
Yang
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.
Philip E
PE
Bourne
D015195:Drug Design; D055106:Genome-Wide Association Study / Q000639:trends*; D023281:Genomics / Q000639:trends*; D059014:High-Throughput Nucleotide Sequencing / Q000639:trends*; D010597:Pharmacogenetics / Q000639:trends*; D057285:Precision Medicine / Q000639:trends*; D013598:Systems Theory