Network Pharmacology and Molecular Docking Analysis of Amoora rohituka Roxb. Reveals Bulnesol Modulates ESR1 and CYP2C19 Proteins as Potential Therapeutic Targets for Neuroprotection in the Management of Depression

Background

Depression is a multifactorial neuropsychiatric disorder involving multiple molecular targets and signalling pathways. Amoora rohituka has a variety of pharmacological properties but its antidepressant activity is still not explored. Hence, the antidepressant effect of A. rohituka was studied in an integrated systems pharmacology approach with a view to understanding the molecular mechanism behind it.

Materials and Methods

The reported phytoconstituents from the leaves of A. rohituka were analysed for drug-likeness, pharmacokinetics, biological activity and adverse drug reactions through public databases. Network pharmacology, Gene Ontology, KEGG pathway enrichment, molecular docking and Prime MM-GBSA analysis were performed on common targets between phytoconstituents and depression.

Results

18 phytoconstituents were identified, out of which twelve were found to be having the drug-likeness properties. The results of network pharmacology revealed 132 common targets, among which MAPK1, AKT1, PARP1, CDK2 and GSK3β were the key proteins in the network hub. KEGG enrichment identified that significant pathways involved such as PI3K-Akt, MAPK, neurotrophin, serotonergic synapse, dopaminergic synapse, mTOR, TNF, NF-κB, JAK-STAT, AMPK and cAMP signalling pathways. Bulnesol, α-guaiene, himachalol, guaiol and β-eudesmol showed good molecular docking interactions with various depression-associated proteins. Bulnesol displayed the best docking scores for ESR1 (-8.20 kcal/mol) and CYP2C19 (-7.242 kcal/mol), and MM-GBSA analysis revealed low binding free energy and stable complexes.

Conclusion

Amoora rohituka has potential antidepressant properties by coordinated modulation of depression associated proteins and signalling pathways. The results of the present study give mechanistic clues and suggest the phytoconstituents to be a promising source for further development of antidepressant drugs.