3D QSAR on a library of heterocyclic diamidine derivatives with antiparasitic activity.
3D QSAR on a library of heterocyclic diamidine derivatives with antiparasitic activity.
复制标题
对具有抗寄生虫活性的杂环二脒衍生物库进行 3D QSAR。
DOI：
10.1016/j.bmc.2005.12.029
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Wilson,WDavid
中科院分区：
文献类型：
--
作者：
Athri,Prashanth;Wenzler,Tanja;Ruiz,Patricia;Brun,Reto;Boykin,DavidW;Tidwell,Richard;Wilson,WDavid
非洲锥虫，布氏罗得西亚锥虫（Trypanosoma brucei rhodesiense，TBR）和布氏冈比亚锥虫（Trypanosoma brucei gambiense，TBG）影响着世界热带地区数十万人的生命。抗结核菌的有效药物戊脒联脒的毒性要求设计更好的药物。联脒的一种口服有效的前药，呋喃脒（DB 75），目前计划进行III期临床试验，对TBG具有优异的活性，毒性低于喷他脒。作为开发针对非洲锥虫的额外和改进的二脒的努力的一部分，已经用呋喃脒和一组25种其他结构相关的化合物进行了CoMFA和CoMSIA 3D QSAR分析。使用了两种不同的比对策略，基于假定的动质体DNA小沟靶标。由于化合物之间保守的静电性质，仅使用空间和电子性质的模型在预测生物学结果方面表现不佳。具有疏水性、供体和受体性质的附加描述符的扩展CoMSIA模型具有良好的预测能力，q2=0.699，r2=0.974，SEE，估计标准误差=0.1，F=120.04。这些结果已被用作设计化合物的指南，这些化合物可能对非洲锥虫具有更好的活性。
African trypanosomes, Trypanosoma brucei rhodesiense (TBR) and Trypanosoma brucei gambiense (TBG), affect hundreds of thousands of lives in tropical regions of the world. The toxicity of the diamidine pentamidine, an effective drug against TBG, necessitates the design of better drugs. An orally effective prodrug of the diamidine, furamidine (DB75), presently scheduled for phase III clinical trials, has excellent activity against TBG with toxicity lower than that of pentamidine. As part of an effort to develop additional and improved diamidines against African trypanosomes, CoMFA and CoMSIA 3D QSAR analyses have been conducted with furamidine and a set of 25 other structurally related compounds. Two different alignment strategies, based on a putative kinetoplast DNA minor groove target, were used. Due to conserved electrostatic properties across the compounds, models that used only steric and electronic properties did not perform well in predicting biological results. An extended CoMSIA model with additional descriptors for hydrophobic, donor, and acceptor properties had good predictive ability with a q2=0.699, r2=0.974, SEE, standard error of estimate=0.1, and F=120.04. The results have been used as a guide to design compounds that, potentially, have better activity against African trypanosomes.