Interaction of Wild Type and V804l and V804m-Mutated Ret Protein Kinase with Emodin: In Silico Approach

Abstract

Medullary thyroid carcinoma (MTC) is a malignant endocrine tumor originating from parafollicular calcitonin-producing C cells. The proto-oncogene RET (REarranged during Transfection) is known as the main actor in the development and outbreak of MTC. Gain of function mutations of RET constitutively activate the receptor which are found to be responsible for the high percentage of MTC cases. The two FDA-approved drugs used for MTC, vandetanib and cabozantinib, are resistant to two mutant variants of RET which are V804L and V804M. In this study, the interactions of emodin, a natural molecule found in plants, with wild-type as well as V804L and V804M-mutated RET kinase were investigated via molecular docking. Pymol was used to create point mutations on wild type RET. Vandetanib and cabozantinib were used as the reference drugs. The binding free energy of vandetanib with wild-type RET, V804L and V804M variants were found to be -9.3, -9.1 and -8.6 kcal/mol. Similarly, the binding free energy of cabozantinib with wild-type RET, V804L and V804M variants were found to be -10.6, -10.4, and -9.5 kcal/mol, respectively. Clearly, the binding affinity of vandetanib and cabozantinib to RET kinase was found to be reduced in mutated variants as compared to wild type. In the meantime, the binding energy between emodin and wild-type RET was shown to be -9.3 kcal/mol. Interestingly, the binding affinity of emodin to V804L and V804M variants was determined to be increased (-9.9 and -9.8 kcal/mol, respectively) compared to wild type. Furthermore, many H-bonds and hydrophobic interactions between emodin and mutated RET variants were shown. Therefore, strong binding affinity of emodin to wild-type and the mutated variants of RET was suggested in this study. In conclusion, emodin was found to be a potential molecule to inhibit RET kinase activity and could be used as a therapeutical agent against medullary thyroid carcinoma.