ABSTRACT
The in silico study of medicinal plants is a rapidly growing field. Techniques such as reverse screening and network pharmacology are used to study the complex cellular action of medicinal plants against disease. However, it is difficult to produce a meaningful visualization of phytochemical-protein interactions (PCPIs) in the cell. This study introduces a novel workflow combining various tools to visualize a PCPI network for a medicinal plant against a disease. The five steps are 1) phytochemical compilation, 2) reverse screening, 3) network building, 4) network visualization, and 5) evaluation. The output is a PCPI network that encodes multiple dimensions of information, including subcellular location, phytochemical class, pharmacokinetic data, and prediction probability. As a proof of concept, we built a PCPI network for bitter gourd (Momordica charantia L.) against colorectal cancer. The network and workflow are available at https://yumibriones.github.io/network/. The PCPI network highlights high-confidence interactions for further in vitro or in vivo study. The overall workflow is broadly transferable and can be used to visualize the action of other medicinal plants or small molecules against other diseases.
ABSTRACT
Brain dopamine-serotonin vesicular transport disease is a rare disease caused by autosomal recessive mutations in the SLC18A2 gene, which encodes the VMAT2 protein. VMAT2 is a membrane protein responsible for vesicular transport of monoamines, and its disruption negatively affects neurotransmission. This results in a severe neurodevelopmental disorder affecting motor skills and development, and causes muscular hypotonia. The condition was initially described in a consanguineous Saudi Arabian family with affected siblings homozygous for a P387L mutation. We subsequently found a second mutation in a New Zealand family (homozygous P237H), which was later also identified in an Iraqi family. Pramipexole has been shown to have some therapeutic benefit. Transgenic Caenorhabditis elegans were developed to model the P237H and P387L mutations. Investigations into dopamine- and serotonin-related C. elegans phenotypes, including pharyngeal pumping and grazing, showed that both mutations cause significant impairment of these processes when compared with a non-transgenic N2 strain and a transgenic containing the wild-type human SLC18A2 gene. Preliminary experiments investigating the therapeutic effects of serotonin and pramipexole demonstrated that serotonin could successfully restore the pharyngeal pumping phenotype. These analyses provide further support for the role of these mutations in this disease.
