Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to beta-secretase
文献类型：期刊论文
| 作者 | Hu, Bin; Xiong, Bing ; Qiu, Bei-Ying; Li, Xin; Yu, Hai-Ping; Xiao, Kun; Wang, Xin; Li, Jia; Shen, Jing-Kang
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2006-12 |
| 卷号 | 27期号:12页码:1586-1593 |
| 关键词 | beta-secretase hydroxyethylene OM99-2 Alzheimer's disease structure-activity relationship |
| ISSN号 | 1671-4083 |
| DOI | 10.1111/j.1745-7254.2006.00432.x |
| 文献子类 | Article |
| 英文摘要 | Aim: To develop probes for detecting the binding specificity between beta-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 beta-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 beta-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 beta-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 (A(3)*B-2) with high potency; further truncation of P-3' gave inhibitor 18 (A(3)*B-1) 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. |
| WOS关键词 | MOLECULAR-DYNAMICS ; ALZHEIMERS-DISEASE ; POTENT INHIBITORS ; DESIGN ; SIMULATIONS ; PROTEIN |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000242221300010 |
| 出版者 | BLACKWELL PUBLISHING |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273427]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Hu, Bin |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Hu, Bin,Xiong, Bing,Qiu, Bei-Ying,et al. Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to beta-secretase[J]. ACTA PHARMACOLOGICA SINICA,2006,27(12):1586-1593. |
| APA | Hu, Bin.,Xiong, Bing.,Qiu, Bei-Ying.,Li, Xin.,Yu, Hai-Ping.,...&Shen, Jing-Kang.(2006).Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to beta-secretase.ACTA PHARMACOLOGICA SINICA,27(12),1586-1593. |
| MLA | Hu, Bin,et al."Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to beta-secretase".ACTA PHARMACOLOGICA SINICA 27.12(2006):1586-1593. |
入库方式： OAI收割
来源：上海药物研究所
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