Table 2: Summary of multi-target drugs/preparations with TCM pharmacology based on ligand-protein networks.

DiseaseMethods and experimentsFormula, herbs, and componentsTCM pharmacologyReference

AIDSExperimentsTanninTannin suppresses the activity of HIV-1 reverse transcriptase, protease, and integrase and cuts off virus fusion and virus entry into the host cells.[90]

AIDSExperimentsMatrine from the root of Sophora flavescens Matrine is effective in inducing T-cell anergy by targeting both the MAPKs pathway and the NFAT pathway.[91]

AntitumorExperimentsPHY906:
Glycyrrhiza uralensis Fisch (G), Paeonia lactiflora Pall (P), Scutelleria baicalensis Georgi (S), and Ziziphus jujuba Mill (Z).
PHY906 reduces CPT-11-induced gastrointestinal toxicity in the treatment of colon or rectal cancer by several mechanisms. It both repairs the intestinal epithelium by facilitating the generation of intestinal progenitor or stem cells and several Wnt signaling components and suppresses inflammatory responses like factor kB, cyclooxygenase-2, and inducible nitric oxide synthase.[92]

Anti-inflammatory and analgesic effectsExperimentsQingfu Guanjieshu (QFGJS): paeonol and other componentsThe pharmacokinetic behavior and metabolites of paeonol are greatly promoted by other components in QFGJS. This may be the result of enhanced adsorption of paeonol in the gastrointestinal tract by P-glycoprotein-mediated efflux change.[93]

Inflammatory and arthritic diseasesExperimentsPaeoniflorin from the root of Paeonia lactiflora and sinomenine from the stem of Sinomenium acutum.Paeoniflorin is markedly enhanced when coadministrated with sinomenine, which promotes intestinal transportation via the inhibition of P-glycoprotein and affects the hydrolysis of paeoniflorin via interaction with b-glycosidase.[94]

Anti-inflammatoryExperimentsHuang-Lian-Jie-Du-Tang (HLJDT): Rhizoma coptidis and Radix scutellariae Baicalein derived from Radix scutellariae showed significant inhibitory effect on 5-LO and 15-LO while coptisine from Rhizoma coptidis showed medium inhibitory effects on LTA(4)H.[95]

Acute promyelocytic leukemia (APL)ExperimentsRealgar-Indigo naturalis: tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T)ATI leads to ubiquitination/degradation of promyelocytic leukemia (PML) retinoic acid receptor oncoprotein, reprogramming of myeloid differentiation regulators, and G1/G0 arrest in APL cells by mediating multiple targets. A acts as the principal component of the formula, whereas T and I serve as adjuvant ingredients.[96]

Chronic myeloid leukemia
(CML)
ExperimentsImatinib (IM) and arsenic sulfide [As(4)S(4) (AS)]AS targets BCR/ABL through the ubiquitination of key lysine residues, leading to its proteasomal degradation, whereas IM inhibits the PI3K/AKT/mTOR pathway.[97]

InflammationPharmacophore-assisted dockingTwelve examples of compounds from CHCDThe screened compounds target cyclooxygenases 1 and 2 (COX), p38 MAP kinase (p38), c-Jun terminal-NH(2) kinase (JNK), and type 4 cAMP-specific phosphodiesterase (PDE4).[98]

Type II diabetes mellitus (T2DM)Molecular docking (LigandFit), clustering, and drug-target network analysis676 compounds in eleven herbs from Tang-min-ling PillsMultiple active components in Tangminling Pills interact with multiple targets. The 37 targets were classified into 3 clusters, and proteins in each cluster were highly relevant to each other. Ten known compounds were selected according to their network attribute ranking in drug-target and drug-drug network. [99]

Cardiovascular diseaseSimilarity search and alignment, docking (LigandFit)Xuefu Zhuyu decoction (XFZYD): 501 compounds, 489 drug/drug-like compoundsActive components in XFZYD mainly target rennin, ACE, and ACE2 in renin-angiotensin system (RAS), which modulates the cardiovascular physiological function.[100]

9 types of cancer, 5 diseases with dysfunction, and 2 cardiovascular disordersDistance-based mutual information model (DMIM)Liu-wei-di-huang formula (LWDH),
Shan-zhu-yu (Fructus Corni), Ze-xie (Rhizoma Alismatis), Dan-pi (Cortex Moutan), Di-huang (Radix Rehmaniae), Fu-ling (Poria Cocos) and Shan-yao (Rhizoma Dioscoreae)
The interactions between TCM drugs and disease genes in cancer pathways and neuro-endocrine-immune pathways were inferred to contribute to the action of LWDH formula.[101]

Cardiovascular diseasesQuantitative composition-activity relationship model (QCAR) (SVM and linear regression)Shenmai, Qi-Xue-Bing-Zhi-Fang (QXBZF)The proportion of active components of Shenmai and QXBZF were optimized based on clinical outcome (collateral and infarct rate of heart) using QCAR. The interactions of multiple weak bindings among different compounds and targets may contribute to the synergetic effect of multicomponent drugs.[102, 103]

AnticoagulantNetwork-based computational scheme utilizing multi-target docking score (LigandFit and AutoDock)Six argatroban intermediates and a series of components from 24 TCMs widely used for cardiac system diseasesA ligand can have impact on multiple targets based on the docking scores, and those with the highest-target network efficiency are regarded as potential anticoagulant agents. Factor Xa and thrombin are two critical targets for anticoagulant compounds and the catalytic reactions they mediate were recognized as the most fragile biological matters in the human clotting cascade system.[104]

Alzheimers’ diseaseSystematical target network analysis frameworkGinkgo biloba, Huperzia serrata, Melissa officinalis, and Salvia officinalis AD-symptoms-associated pathways, inflammation-associated pathways, cancer-associated pathways, diabetes-mellitus-associated pathways, Ca2 -associated pathways, and cell-proliferation pathways are densely targeted by herbal ingredients. [105]

DepressionLiterature search and network analysisHyperforin (HP), hypericin (HY), pseudohypericin (PH), amentoflavone (AF), and several flavonoids (FL) from St. John’s Wort (SJW)Active components in SJW mainly intervene with neuroactive ligand-receptor interaction, the calcium-signaling pathway, and the gap-junction related pathway.
Pertinent targets include NMDA-receptor, CRF1 receptor, 5-hydroxytryptamine receptor 1D, and dopamine receptor D1.
[106]

Rheumatoid arthritis (RA) Integrative platform of TCM network pharmacology including drugCIPHERQing-Luo-Yin (QLY), including four herbs, Ku-Shen (Sophora flavescens), Qing-Feng-Teng (Sinomenium acutum), Huang-Bai (Phellodendron chinensis) and Bi-Xie (Dioscorea collettii), which contain several groups of ingredients such as saponins and alkaloidsThe target network of QLY is involved in RA-related key processes including angiogenesis, inflammatory response, and immune response. The four herbs in QLY work in concert to promote efficiency and reduce toxicity. Specifically, the synergetic effect of Ku-Shen (jun herb) and Qing-Feng-Teng (chen herb) may come from the feedback loop and compensatory mechanisms.[107]