Estudos computacionais de complexo de cobre e paládio II com potencial atividade anticâncer envolvendo a topoisomerase II alfa e as catepsinas B e L
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Data
2023-07-28
Autores
Buanar, Hilário Moniz
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Universidade Estadual Paulista (Unesp)
Resumo
Câncer é considerado umas das principais causas de morte em todo mundo. Conjunto de doenças que faz referência a características comuns, a metástase e a angiogênese. Embora haja uma produção de medicamentos para esta doença, existe baixa seletividade celular por parte dos fármacos comercializados para o tratamento. Com vista a encontrar soluções para o tratamento do câncer, surge a oportunidade de explorar novos complexos inorgânicos, que apresentem seletividade frente as células tumorais. Os complexos de cobre contendo subunidades da tiossemicarbazona e complexos de paládio com subunidades bipiridina e fenantrolina têm sido estudas por possuírem várias aplicações na Química Medicinal. Neste sentido foram ancoradas 32 substâncias para os sítios ativos das catepsinas B e L, assim como para os sítios do etoposídeo e ATP da topoisomerase II alfa. As enzimas proteolíticas como catepsinas (B e L) são ativamente envolvidas em etapas importantes da formação da célula tumoral, enquanto a enzima da topoisomerases II alfa é alvo, devido ao seu papel importante no gerenciamento da estrutura do DNA, em células tumorais, estas proteínas (catepsnia B e L assim como topoisomerase II alfa), são altamente expressas. Inicialmente, foi realizada a validação de modelos in silico para as catepsinas (B e L), visto que, a validação dos sítios do ATP e do etoposídeo haviam sido feitos num outro trabalho pelo nosso grupo de pesquisa. Assim, os resultados da redocagem molecular, possibilitaram analisar as interações dos ligantes com os resíduos de aminoácidos do sítio ativo, onde foi possível verificar sistematicamente interação dos resíduos de aminoácidos, Q23, G27, C29, W30, G73, G74, A173 e G198, do sítio da catepsina B, e a mesma análise foi feita nos resultados do sítio ativo da catepsina L, onde foi possível verificar interação do ligante com os resíduos de aminoácidos de Q19, C25, W26, G61, G67, G68, L69, A135, M161, D162, H163 e A214. Os resultados no sítio ativo do etoposídeo demonstraram interações com os resíduos de Y805, M766 e M762, enquanto no sítio do ATP foram verificadas interações com os resíduos de K378 e N150.
Cancer is considered one of the main causes of death worldwide. It is a group of diseases that refer to common characteristics, metastasis, and angiogenesis. Although there is a production of drugs for this disease, there is low cellular selectivity by the drugs marketed for treatment. To find solutions for cancer treatment, the opportunity arises to explore novel compounds based on transition metals that present selectivity to cells. Copper complexes containing thiosemicarbazone and palladium complexes with bipyridine and phenanthroline subunits have been studied for their various applications in Medicinal Chemistry. In this sense, 32 substances were docked into the active sites of cathepsin B and L, as well as into the active sites of topoisomerase II alpha. Proteolytic enzymes such as cathepsins (B and L) are actively involved in important steps in the formation of tumor cells, while topoisomerases are targets of substances with antitumor activity due to their management of DNA structure, enzymes that are highly expressed in tumor cells. Initially, the validation of in silico models of cathepsins (B and L) was performed, since the ATP and etoposide sites were validated recently in our research group. Thus, the results of molecular redocking made it possible to analyze the interactions of the ligands with the amino acid residues of the active site, where it was possible to systematically verify the interactions involving Q23, G27, C29, W30, G73, G74, A173 and G198, of the cathepsin B site, and the same analysis was performed on the results of the active site of cathepsin L, where it was possible to verify the interaction of the ligands with Q19, C25, W26, G61, G67, G68, L69, A135, M161, D162, H163 and A214. The results at the etoposide active site showed interactions with Y805, M766 and M762, while at the ATP site there were interactions involving K378 and N150.
Cancer is considered one of the main causes of death worldwide. It is a group of diseases that refer to common characteristics, metastasis, and angiogenesis. Although there is a production of drugs for this disease, there is low cellular selectivity by the drugs marketed for treatment. To find solutions for cancer treatment, the opportunity arises to explore novel compounds based on transition metals that present selectivity to cells. Copper complexes containing thiosemicarbazone and palladium complexes with bipyridine and phenanthroline subunits have been studied for their various applications in Medicinal Chemistry. In this sense, 32 substances were docked into the active sites of cathepsin B and L, as well as into the active sites of topoisomerase II alpha. Proteolytic enzymes such as cathepsins (B and L) are actively involved in important steps in the formation of tumor cells, while topoisomerases are targets of substances with antitumor activity due to their management of DNA structure, enzymes that are highly expressed in tumor cells. Initially, the validation of in silico models of cathepsins (B and L) was performed, since the ATP and etoposide sites were validated recently in our research group. Thus, the results of molecular redocking made it possible to analyze the interactions of the ligands with the amino acid residues of the active site, where it was possible to systematically verify the interactions involving Q23, G27, C29, W30, G73, G74, A173 and G198, of the cathepsin B site, and the same analysis was performed on the results of the active site of cathepsin L, where it was possible to verify the interaction of the ligands with Q19, C25, W26, G61, G67, G68, L69, A135, M161, D162, H163 and A214. The results at the etoposide active site showed interactions with Y805, M766 and M762, while at the ATP site there were interactions involving K378 and N150.
Descrição
Palavras-chave
Ancoragem molecular, Complexos de cobre e paládio (II), Catepsina (B, L), Topoisomerase II alfa, Atividade anticâncer, Molecular docking, Copper and palladium (II) complexes, Cathepsin (B, L), Topoisomerase II alpha, Anticancer activity