How can (-)-epigallocatechin gallate from green tea prevent HIV-1 infection? Mechanistic insights from computational modeling and the implication for rational design of anti-HIV-1 entry inhibitors
How can (-)-epigallocatechin gallate from green tea prevent HIV-1 infection? Mechanistic insights from computational modeling and the implication for rational design of anti-HIV-1 entry inhibitors
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DOI：
10.1021/jp0550762
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发表时间：
2006-02-16
影响因子：
3.3
通讯作者：
Zhan, CG
中科院分区：
文献类型：
--
作者：
Hamza, A;Zhan, CG
阻止人类免疫缺陷病毒 1 型 (HIV-1) 进入细胞的可能抑制剂被认为是有希望的下一代抗 HIV-1 药物。非常需要开发一种有效的抑制剂来阻断细胞的糖蛋白CD4与HIV-1的糖蛋白gp120的结合，因为gp120-CD4的结合是HIV-1进入细胞的第一步。最近有报道称，绿茶中的 (-)-表没食子儿茶素没食子酸酯 (EGCG) 是一种阻断 gp120-CD4 结合的抑制剂。但其抑制机制仍不清楚。为了了解抑制机制，本研究进行了广泛的分子对接、分子动力学模拟和结合自由能计算，以预测水中 CD4-EGCG、gp120-CD4 和 gpl20-CD4-EGCG 结合复合物的最有利结构。结果表明，EGCG 与 CD4 的结合方式使得计算出的 gp120 与 CD4-EGCG 复合物的结合亲和力可以忽略不计。因此，EGCG与CD4的良好结合可以有效地阻断gp120-CD4结合。计算出的 CD4-EGCG 结合亲和力（Delta G（结合）= -5.5 kcal/mol，K-d = 94 mu M）与现有实验数据非常一致，表明 EGCG 阻断 CD4-gp120 结合的 IC50 接近 100 mu M。这些结果和见解为未来设计新型、更有效的抑制剂来阻断 gp120-CD4 结合提供了合理的基础。
Possible inhibitors preventing human immunodeficiency virus type 1 (HIV-1) entry into the cells are recognized as hopeful next-generation anti-HIV-1 drugs. It is highly desirable to develop a potent inhibitor blocking binding of glycoprotein CD4 of the cell with glycoprotein gp120 of HIV-1, because the gp120-CD4 binding is the initial step of HIV-1 entry into the cells. It has been recently reported that (-)-epigallocatechin gallate (EGCG) from green tea is an inhibitor blocking gp120-CD4 binding. But the inhibitory mechanism remains unknown. For understanding the inhibitory mechanism, extensive molecular docking, molecular dynamics simulations, and binding free-energy calculations have been performed in this study to predict the most favorable structures of CD4-EGCG, gp120-CD4, and gpl20-CD4-EGCG binding complexes in water. The results reveal that EGCG binds with CD4 in such a way that the calculated binding affinity of gp120 with the CD4-EGCG complex is negligible. So, the favorable binding of EGCG with CD4 can effectively block gp120-CD4 binding. The calculated CD4-EGCG binding affinity (Delta G(bind) = -5.5 kcal/mol, K-d = 94 mu M) is in excellent agreement with available experimental data suggesting IC50 approximate to 100 mu M for EGCG-blocking CD4-gp120 binding. These results and insights provide a rational basis for future design of novel, more potent inhibitors to block gp120-CD4 binding.