INTEGRATIVE NETWORK PHARMACOLOGY AND MOLECULAR DOCKING ANALYSIS TO ELUCIDATE THE MULTI-TARGET MECHANISM OF KOUMINE IN NEUROPATHIC PAIN

Abstract

The neuropathic pain (NP), occurring in 7-10% of the world population, originates from the somatosensory nervous system damage and is poorly treated by conventional drugs with less than 50% response rate. Although its chemical mechanism is unclear, koumine, an indole alkaloid from Gelsemium elegans Benth., showed promise in treating NP. In order to comprehend the multi-target mechanism of koumine in treating NP, this study integrated network pharmacology and molecular docking approaches. Ten overlapping targets between koumine and the target gene list extracted from Gene Cards and OMIM database were found as shared targets for koumine in treating NP. By analysing PPI network with STRING and Cyto-scape tools, four hub genes (KIT, EGFR, SLC6A4, and ABCB1) were selected by Maximal Clique Centrality (MCC). GO analysis indicated that PI3K/PKB signalling pathway, MAPK cascade activation, and serotonergic signalling pathway were important biological processes, with plasma membrane localization and protein tyrosine kinase activity as key cell component and molecular function features. Ten KEGG pathways (adj. p < 0.05) were obtained with PI3K-Akt signalling (-log10p ≈ 1.70) ranked first among all of them. Binding interaction studies showed that the molecule koumine has favourable binding affinity with all the hub proteins, where the strongest affinity is found to be SLC6A4 (-9.011 kcal/mol). ADMET analysis predicted high GI absorption (98.06%), BBB permeability, and drug-likeness based on the rule of five of Lipinski .This study clearly defines the multi-target approach of the drug koumine towards NP, validating its future experimentation.