In silico Approach to Evaluate Molecular Interaction between Lysenin from Lumbricus rubellus and KRAS as Co-chemotherapy Agent of 5-FU in Colorectal Cancer
Agustina Tri Endharti1, Eviana Norahmawati2, Aulia Fahira3
1Department of Parasitology, Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia.
2Department of Anatomical Pathology, Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia.
3Medical Degree Program, Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia.
Abstract
RAS gene mutations, especially KRAS, are most common mutation in colorectal cancer. Mutations cause changes in conformation of KRAS protein, makes it unable to bind with RASGAP that works to turn KRAS off. The main chemotherapy drug for colorectal cancer is 5-fluorouracil (5-FU) which inhibits thymidylate synthase. 5-FU has many side effects, therefore it is necessary to consider a combination therapy with natural chemotherapy agents, one of which is lysenin, found in coelomic fluid from Lumbricus rubellus. The aim of this study was to determine the potential of lysenin bond with KRAS as a way of inhibiting the cancer pathway. This research is an in silico experimental study using PatchDock, FireDock, PyMOL, and LigPlot, while the molecular structures are taken from Pubchem and Uniprot databases. Result from molecular docking indicates that there was a bond between lysenin and KRAS with binding affinity score -14.51 kcal/mol, while RASGAP and KRAS has a binding affinity score 4.32 kcal/mol, but after lysenin binds to KRAS, the binding affinity score of this complex with RASGAP becomes -20.47 kcal/mol which was stronger. In conclusion, it was estimated that lysenin was able to become a bond stabilizer between KRAS and RASGAP, consequently KRAS can be turned off. This mechanism of lysenin which was different from 5-FU was expected to have a synergistic effect in inhibiting colorectal cancer.
Keywords: Colorectal cancer, KRAS, 5-fluorouracil (5-FU), lysenin, Lumbricus rubellus, molecular docking
Topic: Bioinformatics