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mTOR與其抑制物Pyrazolopyrimidines 的三維構效關係...

國立高雄大學生物科技研究所

mTOR與其抑制物Pyrazolopyrimidines 的三維構效關係研究及相對空間位置探討 = A 3D-QSAR Study and Spatial Relation of Pyrazolopyrimidine Analogs and Their Target Protein mTOR

紀錄類型:	書目-語言資料,印刷品 : 單行本
並列題名:	A 3D-QSAR Study and Spatial Relation of Pyrazolopyrimidine Analogs and Their Target Protein mTOR
作者:	張馨文,
其他團體作者:	國立高雄大學
出版地:	[高雄市]
出版者:	撰者;
出版年:	2011[民100]
面頁冊數:	74葉圖，表格 : 30公分;
標題:	mTOR
標題:	mTOR
電子資源:	http://handle.ncl.edu.tw/11296/ndltd/94956691313890539377
附註:	參考書目：葉64-67
摘要註:	mTOR(mammalian target of rapamycin)在生物體中以mTORC1(mammalian target ofrapamycin complex 1)及mTORC2(mammalian target of rapamycin complex 2)兩種不同的形式作用。兩者的訊息傳遞路徑有所不同，但皆與細胞的生長、代謝、增殖等調控息息相關，倘若此部分出現異常，可能導致癌症發生，因此抑制mTOR 可有效控制並治療此類型之癌症。mTOR 抑制物可依作用標的分為兩大類，rapamycin-binding domain 抑制物(又稱rapalogs)及kinase domain(ATP-binding domain)抑制物。前者僅可抑制mTORC1，後者則可同時抑制mTORC1 及mTORC2。因此，近期mTOR 抑制物之設計多以kinase domain作為藥物作用標的。由於mTOR 的kinase domain 與PI3K(phosphoinositol 3-kinase)有高度相似性，通常mTOR kinase domain 抑制物也會對PI3K 造成影響，設計對mTOR 具有選擇性的抑制物可避免這種情況。惠氏研究(Wyeth Research)於2009 年發表一系列對mTOR 有選擇性之kinsae domain抑制物，其對mTOR 及PI3K 的生物活性資料亦非常完整，但是尚無三維構效關係(three-dimensional quantitative structure-activity relationship, 3D-QSAR)方面的分析。本研究將惠氏研究發表83 個pyrazolopyrimidines 抑制物，以3D-QSAR 方式計算其於三維空間中的各特性描述場與抑制能力間的關係。在此同時，以蛋白質同源模擬方法建立出mTOR 的三維結構。將3D-QSAR 模型與mTOR 三維結構疊合，猜測抑制物與目標蛋白可能的結合模式，用以說明3D-QSAR 場圖與目標蛋白間的關係，並將抑制物取代基的特性及相對應的蛋白質部位的特性作系統性的整理。由所建立的3D-QSAR 模型得知，如要增加抑制物對mTOR 的活性，R1 在phenylring之後需加上urea group，以提供氫鍵給體與mTOR 的Asp2195 作用，R2 需設計為piperidine連接pyridine，以提供負電取代基與His2247 作用。避免藥物對PI3K 造成影響，則R1 不宜過長，R2 piperidin 與pyridine 中央應設計為carbonyl group。藉由本研究，希望此模型可為未來mTOR 抑制物之開發提供參考，並對相關病症之治療有所貢獻。 mTOR (mammalian target of rapamycin), a key regulator of growth, metabolism, andproliferation, exists as two forms of protein complexes, mTORC1 (mammalian target ofrapamycin complex 1) and mTORC2 (mammalian target of rapamycin complex 2). SincemTORC1 and mTORC2 are highly involved in mediation of PI3K (phosphoinositol 3-kinase)signaling pathways that are deregulated in human tumors, they have been recognized ascancer treatment targets. According to the inhibition domains, mTOR inhibitors arecategorized into rapamycin-binding domain inhibitors and of kinase domain (ATP-bindingdomain) inhibitors. The former targets at mTORC1, whereas the latter, which has been morewidely studied in recent years, targets at both mTORC1 and mTORC2. Because of closesimilarity between kinase domains of mTOR and PI3K, inhibitors toward mTOR inevitablyshow certain degree of inhibition on PI3K. Delicate design of mTOR inhibitors is expected toachieve a higher therapeutic index for enhanced clinical efficacy.Herein 3D-QSAR (three-dimensional quantitative structure-activity relationship)modeling is applied to investigate 83 pyrazolopyrimidine derivatives, which were publishedin 2009 and expected to serve as selective mTOR kinase domain inhibitors by WyethResearch. Due to the lack of known mTOR structure, homology method is adopted to buildmTOR in complex with one studied compound to provide details of possible binding modeand further to be correlated with the 3D-QSAR models.The constructed models suggest that R1 with a urea-modified benzene moiety enhancesthe hydrogen bonding interaction with mTOR Asp2195, whereas R2 carrying a piperidine inconnection with a pyridine boosts the electrostatic interaction with mTOR His2247. On theother hand, the size of substituent on R1 and the connector between piperidine and pyridineon R2 play essential roles in PI3K/mTOR selectivity.

mTOR與其抑制物Pyrazolopyrimidines 的三維構效關係研究及相對空間位置探討 = A 3D-QSAR Study and Spatial Relation of Pyrazolopyrimidine Analogs and Their Target Protein mTOR
張, 馨文

mTOR與其抑制物Pyrazolopyrimidines 的三維構效關係研究及相對空間位置探討 = A 3D-QSAR Study and Spatial Relation of Pyrazolopyrimidine Analogs and Their Target Protein mTOR / 張馨文撰 - [高雄市] : 撰者, 2011[民100]. - 74葉 ; 圖，表格 ; 30公分.
參考書目：葉64-67.
mTORmTOR

mTOR與其抑制物Pyrazolopyrimidines 的三維構效關係研究及相對空間位置探討 = A 3D-QSAR Study and Spatial Relation of Pyrazolopyrimidine Analogs and Their Target Protein mTOR
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