Estudo semi-emp?rico da intera??o de 20-hidroxiecdisona e seus agonistas sint?ticos com modelos de homologia de receptores de ecdister?ide (EcR),

• Ano de defesa: 2002
• Autor(a) principal: Santos, Ana Cristina Souza dos
• Orientador(a): Sant'Anna, Carlos Mauricio Rabello de
• Banca de defesa: Sant'Anna, Carlos Mauricio Rabello de, Villar, Jos? Daniel Figueroa, Albuquerque, Magaly Gir?o, Echevarria, Aurea, Costa, Jo?o Batista Neves
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal Rural do Rio de Janeiro
• Programa de Pós-Graduação: Programa de P?s-Gradua??o em Qu?mica
• Departamento: Instituto de Ci?ncias Exatas
• País: Brasil
• Palavras-chave em Português: Qu?mica
• Área do conhecimento CNPq: Qu?mica
• Link de acesso: https://tede.ufrrj.br/jspui/handle/jspui/4305

The dibenzoylhydrazines (DBHs) R11-5849, Rtt-5992 (tebulienozide), and RH-2485 (metoxifenozide) are non-steroidal agonists of 20-hydroxyecdysone (20E) insect hormone, that exert their insecticide eflect by interaction with the 20E receptor (EcR). Tebul?nozide and metoxifenozide are selectively toxic to lepidopteran species. In this theoretical study, the DBHs were firstly evaluated by a comparison with the natural agonist (20E) structure. In the next step, the RH-2485 selectivity towards Lepidoptera was studied with models of EcRs of the Lepidoptera Manduca Sexta, andof the Diptera Drosophila melanojzaster. The 3D structures of both EcRs were constructed by homology modeling with the SWISS-MODEL server. The models were constructed from crystallographic coordinates of related proteins ofthe nuclear receptor super Family, which includes the human receptors of vitamin D, retinoic acid, and thyroid hormone. The initial models, aPter a previous optimization by molecular mechanics, were simplified to an internal conserved region, the receptor ligand interaction site (I,IS), identified by comparison with original template proteins. Atter this step, it was implemented a rigid docking study of 20E inside the probable ligand interaction cavity (LIC) of the models. The M. sexta and D. melanogaster LICs were defined by the amino acids that could directly interact with the ligand. The same procedure was employed [br the DBHs RH-5849 and RH-2485. In order to evaluate the interaction pattern inside the EcR LICs, the enthalpy of interaction and the geometry of the ligand/LlC complexes were studied by the semiempirical approach. The ca[culated enthalpies associated with the interaction forces between the synthetic agonists and the amino acids of the LICs are in accordance with the experimental biological activity ofthe DBHs towards Lepidoptera and Diptera. In the following step, an interaction study between the M. sexta LIC (msEcR-LIC) and 10 additional DBHs was implemented to search for correlations between calculated enttlalpy terras associated with the interaction and pLDs0 experimental values of the synthetic agonists [SMAGGHE et al., 1999]. New DBH ligands with potential pesticide activity were proposed alter identification of the important groups for the EcR agonist activity. The interaction of the new ligands (RURAL-l, RURAL-2, and RURAL-3) with the msEcR-LIC amino acids resulted in quite favorable enthalpies, as compared to the known pesticides tebufenozide and metoxifenozide.