Avaliação do perfil metabólico da estavudina através do emprego da bioconversão e da modelagem molecular do citocromo P-450 CYP3A4

• Ano de defesa: 2009
• Autor(a) principal: FREITAS, Lênis Medeiros de
• Orientador(a): OLIVEIRA, Valeria de
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Goiás
• Programa de Pós-Graduação: Mestrado em Ciências Farmacêuticas
• Departamento: Ciências da Saúde - Farmácia
• País: BR
• Palavras-chave em Português: Biotransformação, microrganismos eucarióticos, modelagem molecular, estavudina
• Palavras-chave em Inglês: Biotransformation, eukaryotic microorganisms, molecular modeling, stavudine
• Área do conhecimento CNPq: CNPQ::CIENCIAS DA SAUDE::FARMACIA::FARMACOTECNIA
• Link de acesso: http://repositorio.bc.ufg.br/tede/handle/tde/2132

Before the approval of an active compound, metabolism studies are necessary to ensure its safety, once active metabolites could be synthesized during human biotransformation. The use of eukaryotic microorganisms for the study of drug metabolism has been widely explored, due to its capability of producing metabolites similar to the mammalians, and in silico studies consist in a fast strategy when compared with traditional metabolism studies. In this context, molecular modeling, using docking of molecules of interest in the active site of enzymes involved in drug metabolism, is a useful tool to evaluate the interactions between drug and receptor, because it could predict favorable orientations that could be biotransformated. In this work, sixteen filamentous fungi strains, obtained from collections and isolated from soil in the central Brazil, were evaluated for their capability of the antiretroviral stavudine biotransformation, also complemented by animal metabolism studies and molecular modeling of the most relevant cytochrome P450 isoform of human metabolism: CYP3A4. From the bioconversion experiments, the fungus Cunninghamella elegans ATCC 26169 was capable of metabolize stavudine, forming mammalian metabolites, producing the thymine derivative. Dynamic molecular studies demonstrated that the most probable reactions for stavudine, catalyzed by CYP3A4, involves hydroxylation of methyl group (position C-7) and the double bond epoxidation of the furanic ring, showing the importance of some residues of the active site in this process, like Arg212