基于优势结构片段合理组合的分子杂合策略发现HIV-1抑制剂
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- 英文论文题名：Discovery of HIV-1 inhibitors using molecular hybridization strategy through combining privileged structural features of DAPYs and IASs
- 论文作者：黄伯世 ; 展鹏 ; 刘新泳
- 英文论文作者：Boshi Huang ; Peng Zhan ; Xinyong Liu ; Department of Medicinal Chemistry ; School of Pharmaceutical Sciences ; Shandong University
- 年：2016
- 作者机构：山东大学药学院药物化学研究所;
- 论文关键词：二芳基嘧啶 ; 吲哚芳砜 ; 优势结构片段 ; 分子杂合 ; HIV-1非核苷类逆转录酶抑制剂
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十八分会：化学生物学
- 语种：中文
- 分类号：TQ463.5
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十八分会 ; 化学生物学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：184k
- 原文格式：D
- 会议级别：全国
摘要
二芳基嘧啶(Diarylpyrimidines,DAPY)类化合物,是新近HIV-1非核苷类逆转录酶抑制剂(Non-nucleoside reverse transcriptase inhibitors,NNRTIs)研究领域的热点之一。该类化合物在结合口袋中的构象非常灵活,使得其对大多数突变HIV-1毒株都有很高的抑制活性。目前已有代表化合物Etravirine和Rilpivirine上市。吲哚芳砜(Indolylarylsulfones,IAS)类化合物是另一类新型高效抗HIV-1抑制剂,代表化合物L-737126对HIV-1野生株ⅢB的抑制活性达到纳摩尔级。分子模拟研究发现,L-737126与Rilpivirine在结合口袋中呈现出类似的结合模式和药效团特征,具有三个作用区域:疏水作用区,氢键作用区和可容纳区域Ⅰ。基于以上分析,我们运用分子杂合策略,将Rilpivirine和L-737126分子中的优势结构片段进行合理组合,设计了一系列新型DAPY-IAS杂合体衍生物。细胞水平的抗HIV-1活性结果显示,部分新设计目标化合物对HIV-1野生株ⅢB的抑制活性在微摩尔级,其中活性最好的化合物的EC_(50)值为1.48μM。我们初步探讨了该类化合物的构效关系。DAPY-IAS杂合体衍生物结构新颖,构效关系明确,为进一步修饰该类化合物以提高活性和抗耐药性提供了有益的信息。
Diarylpyrimidine(DAPY) derivatives as HIV-1 NNRTIs with striking activity have attracted considerable attention in recent years.Two most representative DAPYs,etravirine and rilpivirine have been approved by the US FDA for anti-HIV therapy.Indolylarylsulfones(IAS) represented by compound L-737126,are another class of NNRTIs endowed with remarkable anti-HIV-1 activity.Molecular simulation study indicated that L-737126 showed a similar binding mode and pharmacophoric features as rilpivirine.A novel series of DAPY-IAS hybrid derivatives through combining their privileged structural features using molecular hybridization strategy were designed.Some target compounds exhibited moderate activities against HIV-1 ⅢB strain,among which the most potent inhibitor possessed an EC_(50) value of 1.48 μM.Preliminary structure-activity relationships(SARs) are well discussed,providing beneficial information for further modifications.
Diarylpyrimidine(DAPY) derivatives as HIV-1 NNRTIs with striking activity have attracted considerable attention in recent years.Two most representative DAPYs,etravirine and rilpivirine have been approved by the US FDA for anti-HIV therapy.Indolylarylsulfones(IAS) represented by compound L-737126,are another class of NNRTIs endowed with remarkable anti-HIV-1 activity.Molecular simulation study indicated that L-737126 showed a similar binding mode and pharmacophoric features as rilpivirine.A novel series of DAPY-IAS hybrid derivatives through combining their privileged structural features using molecular hybridization strategy were designed.Some target compounds exhibited moderate activities against HIV-1 ⅢB strain,among which the most potent inhibitor possessed an EC_(50) value of 1.48 μM.Preliminary structure-activity relationships(SARs) are well discussed,providing beneficial information for further modifications.
引文
[1]Zhan P.;Chen X.;Li D.;Fang Z.;De Clercq E.;Liu X.Med Res Rev.2013,33 Suppl 1:E1-72.
[2]Li D.;Zhan P.;De Clercq E.;Liu X.J Med Chem.(2012),55:3595-3613.
[2]Li D.;Zhan P.;De Clercq E.;Liu X.J Med Chem.(2012),55:3595-3613.