Systems pharmacology strategies for drug discovery and combination with applications to cardiovascular diseases

Abstract

Ethnopharmacological relevance: Multi-target therapeutics is a promising paradigm for drug discovery which is expected to produce greater levels of efficacy with fewer adverse effects and toxicity than monotherapies. Medical herbs featuring multi-components and multi-targets may serve as valuable resources for network-based multi-target drug discovery.

Materials and methods: In this study, we report an integrated systems pharmacology platform for drug discovery and combination, with a typical example applied to herbal medicines in the treatment of cardiovascular diseases.

Results: First, a disease-specific drug-target network was constructed and examined at systems level to capture the key disease-relevant biology for discovery of multi-targeted agents. Second, considering an integration of disease complexity and multilevel connectivity, a comprehensive database of literature-reported associations, chemicals and pharmacology for herbal medicines was designed. Third, a large-scale systematic analysis combining pharmacokinetics, chemogenomics, pharmacology and systems biology data through computational methods was performed and validated experimentally, which results in a superior output of information for systematic drug design strategies for complex diseases.

Conclusions: This strategy integrating different types of technologies is expected to help create new opportunities for drug discovery and combination.

Keywords: A5L; ADME; Absorption, distribution, metabolism and elimination; Arachidonate 5-lipoxygenase; B1AR; CDK2; CT; CVD; Cardiovascular diseases; Carthamus tinctorius; CgmpA; Cyclin dependent kinase 2; DD network; DSH; DT network; Drug discovery and combination; Drug–drug network; Drug–target network; ERB; Estrogen receptor beta; FC; Fructus Cartaegi; M2; MAPK14; Mitogen-activated protein kinase14; Muscarinic acetylcholine receptor 2; NOSE; Nitric-oxide synthase endothelial; OB; Oral bioavailability; PGS; PPAR; Peroxisome proliferator-activaed receptor gamma; Prostaglandin g/h sythase1; RSM; RSM, FC and CT; Radix Salviae Miltiorrhizae; Systems biology; Systems pharmacology; TS; TT network; TTD; Tanimoto similarity; Target–target network; Therapeutic Target Database; beta-1 adrenergic receptor; cGMP-inhibited 3′,5′-cyclic phosphodiesterase A.