Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking
Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking
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DOI：
10.1021/jm051211n
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发表时间：
2006-04-20
影响因子：
7.3
通讯作者：
Lü, JG
中科院分区：
文献类型：
--
作者：
Sheng, CQ;Zhang, WN;Lü, JG
为了开发高效唑类抗真菌药物，三维定量构效关系方法。CoMFA和CoMSIA，使用一组新的唑类抗真菌化合物。利用柔性对接方法进一步探索了化合物在羊毛甾醇14 α-脱甲基酶活性位点的结合模式。各种疏水性，货车德瓦尔斯，π-π堆积，和氢键相互作用之间的唑类和酶观察。基于分子模拟的结果，建立了基于受体的药效团模型，以指导唑类抗真菌药物的合理优化。通过三步优化设计合成了57个新的唑类化合物。体外抗真菌活性测试表明，这些新的唑类化合物的抗真菌活性得到了很大的提高，从分子模拟的角度证实了模型的可靠性。
In a continuing effort to develop highly potent azole antifungal agents, the three-dimensional quantitative structure-activity relationship methods. CoMFA and CoMSIA, were applied using a set of novel azole antifungal compounds. The binding mode of the compounds at the active site of lanosterol 14 alpha-demethylase was further explored using the flexible docking method. Various hydrophobic, van der Waals,pi-pi stacking, and hydrogen bonding interactions were observed between the azoles and the enzyme. Based on results from the molecular modeling, a receptor-based pharmacophore model was established to guide the rational optimization of the azole antifungal agents. Thus, a total of 57 novel azoles were designed and synthesized by a three-step optimization process. In vitro antifungal assay revealed that the antifungal activities of these novel azoles were greatly improved, which confirmed the reliability of the model from molecular modeling.