In silico kinase inhibition profiling of BRAF and AKT Signaling in Melanoma Cells with Nuciferine

Abstract

The RAS/RAF and PI3K/AKT pathways play a crucial regulatory role and oncogenic mutation of key proteins in these pathways leads to cancer metastasis and chemoresistance. Melanoma is triggered by NRAS and BRAF V600E mutation which causes constitutive activation of the PI3K kinase and BRAF kinase respectively, further leading to oncogenic activation of the AKT kinase and mitogen-activated protein kinase (MAPK). Core regulatory network behind MAPK and AKT cascades interconnect and form feedback loops. This crosstalk between the two pathways plays a vital role in melanoma kinase inhibitor resistance. Nuciferine is found in the plants Nelumbo Nucifera and Nymphaea Caerulea. Nuciferine is the main aporphine alkaloid produced in Nelumbo nucifera. Nuciferine have the best efficiency to remove oxygen free radicals and hydroxyl free radicals. Nuciferine have potent ROS scavenging activity. Nuciferine provokes anti-inflammation, anti-psychotic drug, anti-cancer treatment, and anti-obesity diseases. This in silico analysis results reinforces nuciferine has an effective kinase inhibitor with a potential advantage of evading resistance in melanoma by dual targeting. The residues of the substrate binding pockets were identified using literature search. Molecular docking studies was carried out using AutoDock. Docking studies indicated nuciferine and vemurafenib (reference standard) showed better binding affinity for kinase pockets of Braf V600E, MEK, ERK, PI3K, AKT, mTOR and c-KIT. -7.00Kcal/mol is considered as the cut-off energy for inhibition analysis. Hydrophobic interactions were computed using Biovia. Biovia was used for the graphical representation of protein ligand binding.