Kireev D B, Chrétien J R, Grierson D S, Monneret C
Laboratoire de Chimiométrie, Université d'Orléans, France.
J Med Chem. 1997 Dec 19;40(26):4257-64. doi: 10.1021/jm970110p.
Quantitative structure-activity relationships (QSAR) have been established for 87 analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), a potent inhibitor of the HIV-1 reverse transcriptase (RT). Of these 87 nonnucleoside RT inhibitors, 9 novel HEPT analogues were used in the study and the others were taken from the literature. The predictive ability of these relationships has been evaluated using a large set of 54 compounds which were not used to derive the activity model. Descriptors related to the conformational changes were found to be an important factor which underlies RT inhibitory activity in the HEPT series. Indeed, the QSAR model provides evidence concerning the conformational transformations the molecules may undergo during the inhibition process. The established relationships are supplementary to the experimental study on the binding of HEPT type inhibitors to RT by Hopkins et al. (J. Med. Chem. 1996, 39, 1589-1600). The present study suggests a quantitative interpretation of the structure-activity relationships which otherwise cannot be explained within the framework of the crystal inhibitor-protein model. This information is pertinent to the further design of new HEPT type RT inhibitors.
已针对1-[(2-羟基乙氧基)甲基]-6-(苯硫基)胸腺嘧啶(HEPT，一种有效的HIV-1逆转录酶(RT)抑制剂)的87种类似物建立了定量构效关系(QSAR)。在这87种非核苷RT抑制剂中，9种新型HEPT类似物用于该研究，其他则取自文献。已使用一大组54种未用于推导活性模型的化合物评估了这些关系的预测能力。发现与构象变化相关的描述符是HEPT系列中RT抑制活性的一个重要基础因素。实际上，QSAR模型提供了有关分子在抑制过程中可能经历的构象转变的证据。已建立的关系是对Hopkins等人关于HEPT型抑制剂与RT结合的实验研究的补充(J. Med. Chem. 1996, 39, 1589 - 1600)。本研究提出了对构效关系的定量解释，否则在晶体抑制剂-蛋白质模型的框架内无法解释。该信息与新型HEPT型RT抑制剂的进一步设计相关。
