Systems Approaches And Polypharmacology For Drug Discovery From Licorice

Herb medicines are becoming more mainstream in clinical practice and show the valuein the treating and preventing diseases. However, due to its extreme complexity both inchemical components and mechanisms of action, deep understanding of botanical drugs isstill difficult. Thus, a comprehensive systems approach which could identify activeingredients and their targets in the crude drugs and more importantly, understand thebiological basis for the pharmacological properties of herb medicines is necessary. In thisstudy, a novel systems pharmacology model that integrates oral bioavailability screening,drug-likeness evaluation, blood-brain barrier permeation, target identification and networkanalysis has been established to investigate the herbal medicines. A typical botanic druglicorice is exemplified, which has been widely used in clinics for relieving-cough,anti-inflammatory, anti-anabrosis, immunomodulatory, anti-cancer and the anti-virushepatitis. The main results of the paper are as following:(1) Seventy-three components out of287ingredients (25%) in licorice are identified asactive substances through oral bioavailability and drug-likeness screening. These includemany reported active components as liquiritigenin, glabridin, hispaglabridin A, licochalconeB, glabridin, glycycoumarin, isoliquiritigenin, which further validate the reasonability ofour screening model. In addition, we also predict some molecules such as licoagrocarpin,glyasperins C, morachalcone A, licopyranocoumarin, neoglycyrol, licochalcone G,5’-Prenylbutein as potential bioactive compounds, which might serve to guide our furtherstudy of this botanical drug.(2) The identified91targets related with different diseases are critical forunderstanding the pharmacological mechanisms of licorice. The generated drug-targetnetwork suggests that compounds71(glyasperins C),63(Licoagrocarpin),74(glycyrrhizicacid) and the target proteins PTPN1, HRH1, F2with high degree or betweenness are the keycomponents playing important roles in the drug-target interaction network.(3) The drug-target-disease network clearly elucidates the mechanisms of action oflicorice that exerts various pharmacological effects against diseases including therespiratory, cardiovascular and gastrointestinal system diseases. For example, the licoriceflavonoids mainly target the ischemia-related proteins HTR1A, OPRD1, GSK3B, HRH1, MAPK10, F2, ADRA2A, AChE to achieve the anti-ischemia effects and curing ischemicheart disease. The resulting network lays the foundation for a more comprehensivevisualization of the drug-target-disease interaction landscape.(4) The detoxification mechanism of licorice is also illustrated by the present work. Forinstance, compounds liquiritin and licochalcone G can destroy bacteria by targeting themetalloelastase and strengthen the tissue macrophages to defense against external invasions.