Understanding Molecular Mechanisms Behind the Anti-Inflammatory Effects of Machilus macrantha (Gulmavu) by Network Pharmacology and Molecular Modeling Approach

Inflammation is a critical defense mechanism that mainly occurs in the human body through arachidonic acid metabolism and is needed to maintain a healthy life, but uncontrolled inflammation leads to several diseases like asthma, osteoarthritis, etc. Machilus macrantha is an important Indian medicinal plant that is traditionally used as an anti-inflammatory, anti-rheumatic agent but has yet to be explored much. Hence, this study has been undertaken to elucidate the molecular mechanisms underlying its anti-inflammatory activity by using network pharmacology and molecular modeling studies. Several free online tools and databases like SEA, Swiss target prediction, OMIM, GeneCards, Venny 2.1.0 and STRING were utilized to predict, compile and filter the anti-inflammatory targets and a total of 23 targets were obtained throughout the process. Further, by using the topology parameters (degree, betweenness and closeness) in Cytoscape 3.10.0 software, a total of five hub nodes or genes named PTGS2, NFk beta 1, MAPK1, CYP2C8 and CYP2C9 were identified which is mainly associated with arachidonic acid metabolism. KEGG and GO analyses were performed by using the SRplot tool and it was observed that arachidonic acid metabolism emerged as the top pathway with the lowest P-value and highest fold enrichment. The tissue enrichment studies of the hub genes were also performed using the Human eFP Browser. Finally, a ligand-target-pathway interaction network was created, which proved that the phytoconstituents of M. macrantha interact with multiple molecular targets of arachidonic acid metabolism and showed anti-inflammatory activity. Molecular docking and molecular dynamics simulation studies proved that a total of three ligands named machigline, machiline and quercetin exhibited moderate to good binding affinities toward the hub genes and machigline and quercetin showed stability in the binding cavity. From the present study, it can be concluded that the phytocompounds of M. macrantha have significant interactions with anti-inflammatory targets specifically on arachidonic acid metabolism, hence the same can act as an important source for developing novel anti-inflammatory agents.