EUCALYPTOL AND MELANOMA CELL PROLIFERATION: IN SILICO ANALYSIS

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  • Presentation type: MS - Master's student
  • Track: 1. Bioinformatics
  • Keywords: AutodockVina; Product Of Natural Origin; Skin Cancer;
  • 1 Universidade Federal do Rio Grande

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Abstract

INTRODUCTION AND OBJECTIVES: Melanoma is the most lethal form of skin cancer and the discovery of new drugs is essential for its treatment. The chronic proliferation is one of the characteristics of tumour cells, including the melanoma, that is characterized by the extreme activation of the MAPK pathway (RAS/RAF/MEK/ERK), and is frequently associated with the mutations in the BRAF gene, with the V600E mutation being most common, resulting in the kinase being constantly active. Furthermore, the proliferation of melanoma cells may also be associated with the overexpression of CDK4 and CDK6, which regulate the transition from the phases G1 to S. In vitro studies report the promising effect of eucalyptol in different tumour lineages, however little is known about its possible molecular targets and the effects on melanoma. In this context, the attainment of the data can be optimized by the methodologies in silico, which allows for one to reduce time and costs. Therefore, this work proposes to investigate, through molecular docking simulations, the possible interaction between the eucalyptol ligand and the mutated B-Raf proteins, MEK1/2, ERK1/2, CDK4 and CDK6. MATERIAL AND METHODS: The ligand was acquired from the PubChem database, and the proteins from the PDB database. The ligand was converted to PDB format using the web version of OpenBabel software and prepared in AutodoockTools software. The proteins were prepared in the UCFS Chimera software (ligand deletion) and AutodockTools (water deletion, addition of polar hydrogens, charge stabilization and preparation of simulation boxes covering the entire surface of the proteins). The molecular docking was performed in the AutodockVina software with a thousand rotations of each protein-ligand complex and the complexes were later visualized in the PyMol software. RESULTS AND CONCLUSION: Based on the results obtained in the molecular docking simulations, it was observed that the eucalyptol ligand managed to interact with all the proteins. The most stable interactions were -5.7 kcal/mol for the Braf-eucalyptol complex, -5.6 kcal/mol for the MEK1-eucalyptol complex, -5.8 kcal/mol for the MEK2-eucalyptol complex, -5.5 kcal/mol for the ERK1-eucalyptol complex, -6.6 kcal/mol for the ERK2-eucalyptol complex, -6.8 kcal/mol for the CDK4-eucalyptol complex and -5.1 for the CDK6-eucalyptol complex. Finally, the data suggests that eucalyptol, as it interacted with all the proteins, is an interesting candidate to be used in experiments aimed at repressing the proliferation of melanoma cells.

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Author

Andressa Matsumoto

Boa tarde Murilo! Ótima pergunta! Apenas com os valores de afinidade não é possível saber se uma interação é mais forte quando comparada a outra, no caso teria que fazer uma análise dos tipos de interações que ocorrem (covalente, iônica, etc) entre o ligante e o receptor. Ah, e é possível realizar este tipo de análise com o software PyMol inclusive. Em relação a segunda pergunta, a maioria dos trabalhos (dos poucos que tem) associam o efeito de inibição da proliferação com vias de morte celular e, até então, não me deparei com nenhum trabalho que tenha usado o eucaliptol e feito WB com as proteínas associadas a via da MAP quinase. Porém, achei interessante sua proposta de comparar a interação do eucaliptol com inibidores de cdk4/6!!