Chen Hai-Feng, Fan Bo-Tao, Zhao Chen-Yang, Xie Lan, Zhao Chun-Hong, Zhou Ting, Lee Kuo-Hsiung, Allaway Graham
Department of Chemistry, University Paris 7-Denis Diderot, 1 rue Guy de la Brosse, 75005, Paris, France.
J Comput Aided Mol Des. 2005 Apr;19(4):243-58. doi: 10.1007/s10822-005-4790-2.
Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT. Based on the proposed mechanism, some new structures were designed and predicted by a SVM model. All compounds exhibited potent inhibitory activities against HIV replication in H9 lymphocytes with EC50 values lower than 1.95 microM. The rationality of the method was validated by experimental results.
采用分子对接和分子动力学模拟研究了3',4'-二-O-(S)-樟脑酰-(+)-顺式凯拉内酯（DCK）类似物抗HIV抑制剂与HIV-1逆转录酶（RT）的结合模式。结果表明，DCK的O16与Lys101的NH之间存在强氢键，并且DCK类似物的作用方式可能与其他类型的HIV-1 RT抑制剂相似。对DCK耐药性的研究表明，它对HIV-1 RT最常见的突变K103N没有显著影响。基于提出的作用机制，通过支持向量机（SVM）模型设计并预测了一些新结构。所有化合物在H9淋巴细胞中均表现出对HIV复制的强效抑制活性，EC50值低于1.95 microM。实验结果验证了该方法的合理性。
