Integrating Computational Methods in Network Pharmacology and In Silico Screening to Uncover Multi-targeting Phytochemicals against Aberrant Protein Glycosylation in Lung Cancer

Glycoproteins are an underexploited drug target for cancertherapeutics.In this work, we integrated computational methods in network pharmacologyand in silico docking approaches to identify phytochemicalcompounds that could potentially interact with several cancer-associatedglycoproteins. We first created a database of phytochemicals fromselected plant species, Manilkara zapota (sapodilla/chico), Mangifera indica (mango), Annona muricata (soursop/guyabano), Artocarpus heterophyllus (jackfruit/langka), Lansium domesticum (langsat/lanzones), and Antidesmabunius (bignay), and performed pharmacokinetic analysis todetermine their drug-likeness properties. We then constructed a phytochemical-glycoproteininteraction network and characterized the degree of interactions betweenthe phytochemical compounds and with cancer-associated glycoproteinsand other glycosylation-related proteins. We found a high degreeof interactions from alpha-pinene (Mangifera indica), cyanomaclurin (Artocarpus heterophyllus), genistein(Annona muricata), kaempferol (Annona muricata and Antidesma bunius), norartocarpetin (Artocarpus heterophyllus), quercetin (Annona muricata, Antidesma bunius, Manilkara zapota, Mangifera indica), rutin (Annona muricata, Antidesma bunius, Lansium domesticum), and ellagic acid (Antidesma bunius and Mangifera indica). Subsequent docking analysis confirmedthat these compounds could potentially bind to EGFR, AKT1, KDR, MMP2,MMP9, ERBB2, IGF1R, MTOR, and HRAS proteins, which are known cancerbiomarkers. In vitro cytotoxicity assays of the plantextracts showed that the n-hexane, ethyl acetate,and methanol leaf extracts from A. muricata, L. domesticum and M. indica gave the highestgrowth inhibitory activity against A549 lung cancer cells. These mayhelp further explain the reported cytotoxic activities of select compoundsfrom these plant species.