Traditional Chinese medicine application in HIV: an in silico study
Traditional Chinese medicine application in HIV: an in silico study
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DOI：
10.1080/07391102.2012.745168
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发表时间：
2014-01-02
影响因子：
4.4
通讯作者：
Chen, Calvin Yu-Chian
中科院分区：
文献类型：
--
作者：
Huang, Hung-Jin;Jian, Yi-Ru;Chen, Calvin Yu-Chian
人类免疫缺陷病毒（HIV）的病毒感染需要将病毒DNA与宿主DNA整合在一起，宿主DNA涉及HIV积分酶（IN）与其coctor透镜上皮衍生的生长因子（LEDGF/p75）的结合。由于与LEDGF/p75的IN结合破坏了抑制HIV的增殖，因此IN的抑制或变性是抑制HIV复制的一种方法。 D77是一种已知的药物，通过与IN结合，证明对HIV的抑制作用。本文中，我们利用D77作为筛查传统中药（TCM）化合物，具有相似的原子水平特征。发现9-羟基（10E） - 二十二烯酸和Beauveriolide I通过虚拟筛选的码头得分高于D77的码头得分。多个线性回归（R2 = 0.9790）和支持向量机（R2 = 0.9114）模型始终预测TCM候选者的潜在生物活性。 40 NS分子动力学模拟表明，TCM化合物满足了与IN形成稳定复合物的药物样标准。原子水平的研究表明，与重要残基A：lys173结合的9-羟基（10E） - 二十二烯酸和Beauveriolide I与核心Ledgf结合位点以及LEDGF上的In In In In In In In In In In In In In In In In In In In bindgf。 TCM候选者还启动了可能影响IN功能的螺旋丢失。共处，9-羟基 - （10E） - 二十二烯酸和beauveriolide i至（1）形成稳定的相互作用，影响影响内在结合的稳定互动和（2）可以预测TCM候选者可能会在contection中遇到的潜在的启动结构，这些既可能会构成IS的潜在启动结构。 proteopedia http://proteopedia.org/w/journal:jbsd:40
Viral infection by human immunodeficiency virus (HIV) requires integration of viral DNA with host DNA which involves the binding of HIV integrase (IN) with its co-factor lens epithelium-derived growth factor (LEDGF/p75). Since disrupted binding of IN with LEDGF/p75 inhibits proliferation of HIV, inhibition or denaturation of IN is a possible method for inhibiting HIV replication. D77 is a known drug with demonstrated inhibition against HIV by binding to IN. Herein, we utilized D77 as a control to screen for traditional Chinese medicine (TCM) compounds that exhibit similar atomic-level characteristics. 9-Hydroxy-(10E)-octadecenoic acid and Beauveriolide I were found to have higher Dock Scores to IN than D77 through virtual screening. Multiple linear regression (R2=0.9790) and support vector machine (R2=0.9114) models consistently predicted potential bioactivity of the TCM candidates against IN. The 40 ns molecular dynamics simulation showed that the TCM compounds fulfilled the drug-like criteria of forming stable complexes with IN. Atomic-level investigations revealed that 9-hydroxy-(10E)-octadecenoic acid bound to an important residue A:Lys173, and Beauveriolide I formed stable interactions with the core LEDGF binding site and with Asn256 of the IN binding site on LEDGF. The TCM candidates also initiated loss of -helices that could affect the functionality of IN. Taken together, the ability of 9-hydroxy-(10E)-octadecenoic acid and Beauveriolide I to (1) form stable interactions affecting IN-LEDGF binding and (2) have predicted bioactivity against IN suggests that the TCM candidates might be potential starting structures for developing compounds that may disrupt IN-LEDGF binding.An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:40