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제109회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Structure Guided Synthesis of Ixoazole Library and Discovery of PPARγ-Selective Agonists

2012년 2월 29일 16시 10분 24초
MEDI.P-1031 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
4월 25일 (수요일) 18:00~21:00
저자 및
고민섭, 박종민, 구자영, 박승범
서울대학교 화학부, Korea
The peroxisome proliferator-activated receptors (PPARs) have been focused due to their roles related to the glucose, lipid, and lipoprotein homeostasis. There are three PPAR subtypes (termed PPAR alpha, PPAR delta, and PPAR gamma) according to their distinct genetic profiles. Among them, PPAR gamma activation via small molecule ligands has important pharmaceutical meaning for the control of metabolic disorders, cancer and inflammation. We designed ligand library based on the crystal structures of ligand binding domain of the PPARs. Because conventional PPAR ligand has common molecular framework, (1) an acidic head part, (2) a linker part, (3) a hydrophobic tail part, we designed our molecular library mainly based on those characters. Especially, we focused on the linker part and hydrophobic tail part. The key moiety of the ligand is isoxazole and N-carbamoylated urethane, which can give the additional hydrogen bonding and enhances hydrophobic interation. Primary round of moiety selection was performed using the transactivation reporter assay result of simple carbamate library. We concluded that the PPAR gamma can be a selective target out of the other subtypes and the ethyl substituent is the best option for fitting to the middle region of the PPAR gamma active site and subsequent activation. Next, we introduced carbamoyl moiety to the tail part for make enhanced fitting. Finally, we discovered PPAR gamma selective agonist with single digit nanomolar activity. This discovery demonstrated that computational chemistry combined with rational design and combinatorial chemistry is a powerful tool to decipher the complex structure-activity relationship.