Global Mapping of Traditional Chinese Medicine into Bioactivity Space and Pathways Annotation Improves Mechanistic Understanding and Discovers Relationships between Therapeutic Action (Sub)classes

Abstract

Traditional Chinese medicine (TCM) still needs more scientific rationale to be proven for it to be accepted further in the West. We are now in the position to propose computational hypotheses for the mode-of-actions (MOAs) of 45 TCM therapeutic action (sub)classes from in silico target prediction algorithms, whose target was later annotated with Kyoto Encyclopedia of Genes and Genomes pathway, and to discover the relationship between them by generating a hierarchical clustering. The results of 10,749 TCM compounds showed 183 enriched targets and 99 enriched pathways from Estimation Score ≤ 0 and ≥ 5% of compounds/targets in a (sub)class. The MOA of a (sub)class was established from supporting literature. Overall, the most frequent top three enriched targets/pathways were immune-related targets such as tyrosine-protein phosphatase nonreceptor type 2 (PTPN2) and digestive system such as mineral absorption. We found two major protein families, G-protein coupled receptor (GPCR), and protein kinase family contributed to the diversity of the bioactivity space, while digestive system was consistently annotated pathway motif, which agreed with the important treatment principle of TCM, “the foundation of acquired constitution” that includes spleen and stomach. In short, the TCM (sub)classes, in many cases share similar targets/pathways despite having different indications.

Associating 197 Chinese herbal medicine with drug targets and diseases using the similarity ensemble approach

“…In recent decades, ligand-based techniques have been developed and applied to reveal the possible associations between CHM and drug targets. For instance, Zobir et al studied the mode of action of 45 TCM therapeutic action classes by in silico target prediction algorithms, of which the targets were annotated with the Kyoto Encyclopedia of Genes and Genomes pathway [ 14 ]. Huang et al used a most-similar ligand-based approach to predict the mechanism of action targets of aloe-emodin discovered from phenotypic screening and traditional medicine [ 15 ].…”

Orthologue chemical space and its influence on target prediction

“…Another application of target prediction is the extension of predicted bioactivity profiles with gene-pathway and gene-disease associations, to better rationalize the mode-of-action of compounds ( Mohamad Zobir et al , 2016 ). On this topic, we analyzed the impact of the new 51 models, in terms of the improved pathway coverage from BioSystems ( Coordinators, 2013 ) and diseases from DisGeNET ( Piñero et al , 2017 ).…”

Efficacy of Dialectical Comprehensive Treatment of Traditional Chinese Medicine in Patients with Chronic Stable Heart Failure: A Randomized Controlled Trial

“…For example, “Wood” stands for the liver and gall bladder; “Fire” stands for the heart and small intestine; “Earth” stands for the spleen and stomach; “Metal” stands for the lung and large intestine; and “Water” stands for the kidney and urinary bladder [ 32 ]. When the human body suffers from a disease, the dynamic balance of yin-yang and five elements are disturbed [ 33 ]; therefore, in order to correct this disturbance, TCM adopts an overall method (i.e., SDT) to make a specific treatment plan for the disease [ 34 , 35 ]. And, the expert consensus on TCM diagnosis and treatment of CHF published in 2014 gradually unified the classification of TCM syndrome types of HF, which divided HF into three basic syndrome types (qi deficiency and blood stasis type, qi and yin deficiency and blood stasis type, and yang qi deficiency and blood stasis type) [ 36 ].…”