3-DIMENSIONAL STRUCTURE-ACTIVITY ANALYSIS OF A SERIES OF PORPHYRIN DERIVATIVES WITH ANTI-HIV-1 ACTIVITY TARGETED TO THE V3 LOOP OF THE GP120 ENVELOPE GLYCOPROTEIN OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1
3-DIMENSIONAL STRUCTURE-ACTIVITY ANALYSIS OF A SERIES OF PORPHYRIN DERIVATIVES WITH ANTI-HIV-1 ACTIVITY TARGETED TO THE V3 LOOP OF THE GP120 ENVELOPE GLYCOPROTEIN OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1
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DOI：
10.1021/jm00034a007
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发表时间：
1994-04-15
影响因子：
7.3
通讯作者：
NEURATH, AR
中科院分区：
文献类型：
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作者：
DEBNATH, AK;JIANG, S;NEURATH, AR
采用比较分子场分析（CoMFA）方法，建立了21个具有抗HIV-1活性的卟啉衍生物与HIV-1包膜糖蛋白gp 120的V3环结合的三维定量构效关系（3D-QSAR）模型。PLS交叉验证的r（cv）（2）（0.590），表明该模型可以作为一个预测工具，进一步设计卟啉类似物。该模型揭示了至少三个重要的网站，有利的静电相互作用，并表示有利和不利的空间相互作用网站。发现gp 120 V3环序列的固定位置上至少有三个带正电荷的氨基酸残基和几个疏水氨基酸残基是高度保守的。这可能支持所提出的模型的有效性和假设，含有阴离子和疏水基团的卟啉可能与一些高度保守的带正电荷和疏水性的网站，分别的V3环。这些相互作用可诱导gp 120包膜糖蛋白的构象变化，导致抑制病毒进入细胞和合胞体形成（细胞与细胞融合），从而抑制病毒复制。
Using comparative molecular field analysis (CoMFA), a 3D-QSAR model was developed for 21 porphyrin derivatives which have anti-HIV-l activity and bind to the V3 loop of the envelope glycoprotein gp120 of the human immunodeficiency virus type 1. A significant PLS cross-validated r(cv)(2) (0.590) was obtained, indicating that the model could be used as a predictive tool for further design of porphyrin analogs. The model revealed at least three important sites for favorable electrostatic interactions and indicated favorable and unfavorable steric interaction sites. It was found that the occurrence of at least three positively charged and several hydrophobic amino acid residues is highly conserved at fixed positions of gp120 V3 loop sequences. This may support the validity of the proposed model and the hypothesis that porphyrins containing anionic and hydrophobic groups may interact with some of the highly conserved positively charged and hydrophobic sites, respectively, of the V3 loop. These interactions may induce conformational changes in the gp120 envelope glycoprotein leading to inhibition of virus entry into cells and of syncytium formation (cell-to-cell fusion) and thus to inhibition of virus replication.