Joao H C, De Vreese K, Pauwels R, De Clercq E, Henson G W, Bridger G J
Sandoz Research Institute, Vienna, Austria.
J Med Chem. 1995 Sep 15;38(19):3865-73. doi: 10.1021/jm00019a017.
This work describes a study of quantitative structural activity relationships (QSAR) of bis-tetraazamacrocyclic compounds. These compounds represent a novel class of very potent and selective anti-HIV inhibitors, with a new mode of action. The QSAR study correlates structural features of the compounds with anti-HIV activity, resulting in a model which has a high predictive capacity (predictive r2 = 0.79). This predictive model will be of major importance for the design of new anti-HIV inhibitors of this class. Use is made of partial least-squares (PLS) analysis, with the novelty being that structural features derived by inclusion of all sterically allowed conformations for each molecule are included in the analysis. PLS analysis was made of descriptors, including structural parameters, macrocyclic ring size, metal chelating ability, etc., and those features necessary for the observed antiviral activities of these compounds were deduced from the models. Since all sterically allowed conformations are included in the analysis, the flexibility of the molecules is also taken into account. In addition, a correlation is found (indicated by a predictive r2 value of 0.61) between inhibition of HIV-1 (HIV-2) and syncytium formation inhibition in the presence of bis-cyclam analogues, leading to the suggestion of a common target, namely, gp120, being involved in both inhibition of virus replication and syncytium formation.
这项工作描述了对双四氮杂大环化合物的定量构效关系（QSAR）的研究。这些化合物代表了一类新型的非常有效的选择性抗HIV抑制剂，具有一种新的作用模式。QSAR研究将化合物的结构特征与抗HIV活性相关联，得出了一个具有高预测能力的模型（预测r2 = 0.79）。这个预测模型对于设计此类新型抗HIV抑制剂将具有重要意义。采用了偏最小二乘法（PLS）分析，其新颖之处在于分析中纳入了通过包含每个分子的所有空间允许构象而得出的结构特征。对描述符进行了PLS分析，包括结构参数、大环环大小、金属螯合能力等，并从模型中推导了这些化合物观察到的抗病毒活性所需的那些特征。由于分析中纳入了所有空间允许构象，分子的灵活性也得到了考虑。此外，在双环胺类似物存在的情况下，发现HIV-1（HIV-2）抑制与合胞体形成抑制之间存在相关性（预测r2值为0.61），这表明存在一个共同靶点，即gp120，它参与病毒复制抑制和合胞体形成。
