constructionofasmallpeptidelibraryrelatedtoinhibitorom992anditsstructureactivityrelationshiptobsecretase

	constructionofasmallpeptidelibraryrelatedtoinhibitorom992anditsstructureactivityrelationshiptobsecretase
	Bin Hu; Bing Xiong; Beiying Qiu; Xin Li; Haiping Yu; Kun Xiao; Xin Wang; Jia Li; Jingkang Shen
刊名	actapharmacologicasinica
	2006
卷号	27 期号:12 页码:1586
关键词	b-secretase hydroxyethylene OM99-2 Alzheimer's disease structure_activity relationship
ISSN号	1671-4083
英文摘要	Aim: To develop probes for detecting the binding specificity between b-secretase and substrate, and provide reliable biological activity data for further researching encircling substrate-based inhibitors. Methods: To prepare the inhibitors, the hydroxyethylene (HE) segment including P_1 and P_1~' was synthesized after multi-step reactions; the combination of all segments was then completed through solid phase synthesis. Recombinant human b-secretase ectodomain (amino acid residues 1_460) was expressed as a secreted protein with a C-terminal His tag in insect cells using baculovirus infection, and all compounds were evaluated in this b-secretase enzyme assay. In order to understand the interaction in detail, the theoretical methods, namely molecular dynamics (MD) simulation and molecular mechanics-generalized-born surface area (MM-GBSA) analysis, were performed on the complex of b-secretase and OM99-2 to obtain the geometrical and energetical information. Results: We designed and constructed a positional scanning combinatorial library including 16 compounds; all members of the library were synthesized based on HE dipeptide isostere. Structure-activity relationship studies at the P_4~-P_1 and P_1~'-P_4~' positions led to the discoveries of P and P' sides binding specificity and potent inhibitors 14, 18, and 22. The binding free energy on the whole system and every residue were compared to the biological assay result. Conclusion: The removal of P_4~' yielded inhibitor 22 (A3B2) with high potency; further truncation of P_3~' gave inhibitor 18(A3B1) with equal activity, implying that the right side of the inhibitors play a less important role and could be easily simplified, while change on the P side may cause substantial results.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/287735]
专题	中国科学院上海药物研究所
作者单位	中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Bin Hu,Bing Xiong,Beiying Qiu,et al. constructionofasmallpeptidelibraryrelatedtoinhibitorom992anditsstructureactivityrelationshiptobsecretase[J]. actapharmacologicasinica,2006,27(12):1586.
APA	Bin Hu.,Bing Xiong.,Beiying Qiu.,Xin Li.,Haiping Yu.,...&Jingkang Shen.(2006).constructionofasmallpeptidelibraryrelatedtoinhibitorom992anditsstructureactivityrelationshiptobsecretase.actapharmacologicasinica,27(12),1586.
MLA	Bin Hu,et al."constructionofasmallpeptidelibraryrelatedtoinhibitorom992anditsstructureactivityrelationshiptobsecretase".actapharmacologicasinica 27.12(2006):1586.