近來, 大連理工大學(xué)生命學(xué)院的楊永亮博士及課題組開展的"計(jì)算機(jī)輔助藥物設(shè)計(jì)及篩選新技術(shù)研究"取得階段性進(jìn)展, 其研究論文《通過在虛擬篩選中考慮蛋白靶點(diǎn)柔性來確定BACE-1的分子影像探針》(Identification of putative molecular imaging probes for BACE-1 by accounting for protein flexibility in virtual screening)于2012年1月被Journal of Alzheimer's Disease雜志發(fā)表,，詳細(xì)闡述了如何基于靶點(diǎn)全面柔性的新型藥物篩選技術(shù)來確定可以應(yīng)用于阿爾茲海默癥早期診斷的PET成像分子探針。
文章的第一作者為大連理工大學(xué)生命學(xué)院研究生郎海靜, 共同合作作者為美國麻省總醫(yī)院神經(jīng)化學(xué)實(shí)驗(yàn)室主任黃旭東博士,。
阿爾茲海默癥(Alzheimer's disease, AD)是一種漸進(jìn)性,、神經(jīng)退行性疾病, 目前為止還沒有有效的治療藥物或治療措施, 因此對阿爾茲海默癥的早期檢測及診斷顯得尤為重要。β淀粉樣蛋白沉淀是阿爾茲海默癥發(fā)生和發(fā)展的標(biāo)志, 而BACE-1是β淀粉樣蛋白沉淀產(chǎn)生所必需的, 大量證據(jù)顯示在患有阿爾茲海默癥的大腦中BACE-1的表達(dá)水平也明顯提高。因此, BACE-1不僅可以作為阿爾茲海默癥的藥物干預(yù)靶點(diǎn)也可以作為早期診斷靶點(diǎn)。過去的大部分研究發(fā)現(xiàn)的分子探針都是以患者大腦中的淀粉樣沉淀為靶點(diǎn),。另外, 傳統(tǒng)分子探針的發(fā)現(xiàn)途徑耗時、昂貴而且準(zhǔn)確性不高,。
為了提高對阿爾茲海默癥早期檢測的準(zhǔn)確性并發(fā)現(xiàn)有效的診斷探針, 楊永亮博士及其研究團(tuán)隊(duì)以藥物虛擬篩選技術(shù)為基礎(chǔ), 在虛擬篩選分子探針的過程中全面考慮了受體大分子局部或者整體結(jié)構(gòu)的蛋白柔性, 從而大大增強(qiáng)了篩選結(jié)果的精確性。這主要是因?yàn)榕潴w和受體之間的相互作用是動態(tài),、復(fù)雜的, 靶點(diǎn)蛋白分子在與配體分子結(jié)合后多會發(fā)生結(jié)構(gòu)重排或結(jié)構(gòu)域的改變等等, 因此在藥物設(shè)計(jì)與篩選過程中必須全面考慮靶點(diǎn)蛋白的柔性,。研究人員首先基于美國國立衛(wèi)生研究院創(chuàng)立的MICAD數(shù)據(jù)庫(Molecular Imaging and Contrast Agent Database)構(gòu)建了一個虛擬配體分子庫, 配體分子庫中包括同位素76Br、11C、64Cu,、18F標(biāo)記的共283個分子探針,。接下來，為了在虛擬篩選的過程中全面體現(xiàn)蛋白柔性, 研究人員從PDB(Protein Date Bank)數(shù)據(jù)庫中搜集了143個BACE-1的復(fù)雜物晶體結(jié)構(gòu)并組成了一個靶點(diǎn)集合(Ensemble), 應(yīng)用這個靶點(diǎn)分子集合對構(gòu)建的配體分子庫進(jìn)行篩選并得到篩選矩陣,。經(jīng)分析, 最終得到了4個親和力均為納摩爾級別的分子探針, 對這些潛在分子探針有效性的驗(yàn)證正在進(jìn)行中,。
該研究的發(fā)現(xiàn)將會為阿爾茲海默癥的早期檢測提供臨床上的有用的PET探針結(jié)構(gòu), 對AD的早期檢測和治療起到積極推動的作用。另外, 該研究所采用的基于靶點(diǎn)全面柔性的新型篩選技術(shù)對創(chuàng)新藥物的篩選和發(fā)現(xiàn)提供了良好的思路,。(生物谷 Bioon.com)
doi:10.3233/JAD-2011-111787
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Identification of Putative Molecular Imaging Probes for BACE-1 by Accounting for Protein Flexibility in Virtual Screening
Haijing Lang, Xudong Huang, Yongliang Yang
β-secretase (BACE-1), an enzyme critical in the process of amyloid-β (Aβ) peptides deposition in human brain, is closely associated with the onset and progression of Alzheimer's disease (AD). A strong need exists, therefore, to identify molecular imaging probes homing at BACE-1 for use with positron emission tomography (PET) that is recognized as an effective tool for detecting AD. Through this imaging, an early diagnosis of AD could be made. Herein, to identify suitable molecular probes for use with PET, we searched the Molecular Imaging and Contrast Agent Database (MICAD), an online database warehousing scientific information regarding molecular imaging and contrast agents, and applied a virtual screening approach against the different confirmations of BACE-1 obtained from the World Wide Protein Database. The lack of considering receptor flexibility is a key drawback in virtual screening for drug discovery. Therefore, we incorporated protein flexibility into the virtual screening by using an ensemble of 143 experimental BACE-1 structures derived from the Protein Data Bank. Finally, the best performing affinity was recorded and used in the ranking of each ligand. To the best of our knowledge, this is the first virtual screening approach used to identify four new molecular probes that could target BACE-1 with favorable affinity, a discovery that can lead to the development of new PET probes for the early detection and therapy of AD. However, the actual utility of these probes can only be ascertained after in vitro and in vivo investigations.
