Abstract
This network-based pharmacology study intends to uncover the underlying mechanisms of cannabis leading to a therapeutic benefit and the pathogenesis for a wide range of diseases claimed to benefit from or be caused by the use of the cannabis plant. Cannabis contains more than 600 chemical components. Among these components, cannabinoids are well-known to have multifarious pharmacological activities. In this work, twelve cannabinoids were selected as active compounds through text mining and drug-like properties screening and used for initial protein-target prediction. The disease-associated biological functions and pathways were enriched through GO and KEGG databases. Various biological networks [i.e., protein-protein interaction, target-pathway, pathway-disease, and target-(pathway)-target interaction] were constructed, and the functional modules and essential protein targets were elucidated through the topological analyses of the networks. Our study revealed that eighteen proteins (CAT, COMT, CYP17A1, GSTA2, GSTM3, GSTP1, HMOX1, AKT1, CASP9, PLCG1, PRKCA, PRKCB, CYCS, TNF, CNR1, CNR2, CREB1, GRIN2B) are essential targets of eight cannabinoids (CBD, CBDA, Δ9-THC, CBN, CBC, CBGA, CBG, Δ8-THC), which involve in a variety of pathways resulting in beneficial and adverse effects on the human body. The molecular docking simulation confirmed that these eight cannabinoids bind to their corresponding protein targets with high binding affinities. This study generates a verifiable hypothesis of medical benefits and harms of key cannabinoids with a model which consists of multiple components, multiple targets, and multiple pathways, which provides an important foundation for further deployment of preclinical and clinical studies of cannabis.
Highlights
Cannabis is an annual herbaceous flowering plant in the Cannabaceae family
Where ICi refers to the integrated centrality of target i; DCi, BCi, CCi, and ECi refer to the degree, betweenness, closeness, and eigenvector centralities of target i; DCmin, BCmin, CCmin, and ECmin refer to the minimum degree, betweenness, closeness, and eigenvector centralities of the functional module; and DCmax, BCmax, CCmax, and ECmax refer to the maximum degree, betweenness, closeness, and eigenvector centralities of the functional module
There are increasing pieces of evidence that the medicinal properties of Cannabis mainly come from cannabinoids [39]
Summary
While there are differences in chemical contents and plant domestication phases Cannabis can be grouped into three types according to the contents of its main cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD): Type I, high THC (>0.3%) and low CBD (0.3%) and high CBD (>0.5%); and Type III, low THC (0.5%) [3]. Cannabis can be produced in two major categories: marijuana (Types I and II) and hemp (Type III) [4]. Cannabisbased products are documented to have both beneficial and adverse effects. The beneficial effects include treating various diseases, such as cancers, inflammation, pains, epilepsy, Parkinson’s, Alzheimer’s, multiple sclerosis, chronic spasticity, etc., (Table 1(A)); whereas the adverse effects include respiratory and cardiovascular diseases, psychiatric comorbidities, addiction, and impairment of brain development, etc., (Table 1(B)). Cannabis use disorders and withdrawal symptoms: dizziness, dry mouth, somnolence, and confusion; restless, irritability, mild agitation, insomnia, nausea, and cramping
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