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Using computational docking and virtual screening techniques the characterization of the Trypanosoma brucei pteridine reductase active-site.
Current Computer-Aided Drug Design ( IF 1.7 ) Pub Date : 2020-09-30 , DOI: 10.2174/1573409915666190827163327
Hina Shamshad 1 , Abdul Hafiz 2 , Ismail I Althagafi 3, 4 , Maria Saeed 5 , Agha Zeeshan Mirza 3, 4
Affiliation  

Background: Human African trypanosomiasis is a fatal disease prevalent in approximately 36 sub-Saharan countries. Emerging reports of drug resistance in Trypanosoma brucei are a serious cause of concern as only limited drugs are available for the treatment of the disease. Pteridine reductase is an enzyme of Trypanosoma brucei.

Methods: It plays a critical role in the pterin metabolic pathway that is absolutely essential for its survival in the human host. The success of finding a potent inhibitor in structure-based drug design lies within the ability of computational tools to efficiently and accurately dock a ligand into the binding cavity of the target protein. Here we report the computational characterization of Trypanosoma brucei pteridine reductase (Tb-PR) active-site using twenty-four high-resolution co-crystal structures with various drugs. Structurally, the Tb-PR active site can be grouped in two clusters; one with high Root Mean Square Deviation (RMSD) of atomic positions and another with low RMSD of atomic positions. These clusters provide fresh insight for rational drug design against Tb-PR. Henceforth, the effect of several factors on docking accuracy, including ligand and protein flexibility were analyzed using Fred.

Results: The online server was used to analyze the side chain flexibility and four proteins were selected on the basis of results. The proteins were subjected to small-scale virtual screening using 85 compounds, and statistics were calculated using Bedroc and roc curves. The enrichment factor was also calculated for the proteins and scoring functions. The best scoring function was used to understand the ligand protein interactions with top common compounds of four proteins. In addition, we made a 3D structural comparison between the active site of Tb-PR and Leishmania major pteridine reductase (Lm- PR). We described key structural differences between Tb-PR and Lm-PR that can be exploited for rational drug design against these two human parasites.

Conclusion: The results indicated that relying just on re-docking and cross-docking experiments for virtual screening of libraries isn’t enough and results might be misleading. Hence it has been suggested that small scale virtual screening should be performed prior to large scale screening.



中文翻译:

使用计算对接和虚拟筛选技术表征布氏锥虫蝶啶还原酶活性位点。

背景:非洲人类锥虫病是一种在大约 36 个撒哈拉以南国家流行的致命疾病。布鲁氏锥虫耐药性的新报告是一个严重的问题,因为只有有限的药物可用于治疗这种疾病。蝶啶还原酶是布氏锥虫的一种酶。

方法:它在蝶呤代谢途径中起着关键作用,这对其在人类宿主中的生存是绝对必要的。在基于结构的药物设计中找到有效抑制剂的成功在于计算工具能够有效且准确地将配体停靠到目标蛋白的结合腔中。在这里,我们报告了布氏锥虫蝶啶还原酶 (Tb-PR) 活性位点的计算表征,使用 24 种高分辨率共晶结构与各种药物。在结构上,Tb-PR 活性位点可以分为两个集群;一种具有高原子位置均方根偏差 (RMSD),另一种具有低原子位置 RMSD。这些集群为针对 Tb-PR 的合理药物设计提供了新的见解。今后,几个因素对对接精度的影响,

结果:在线服务器用于分析侧链灵活性,并根据结果选择四种蛋白质。使用 85 种化合物对蛋白质进行小规模虚拟筛选,并使用 Bedroc 和 roc 曲线计算统计数据。还计算了蛋白质和评分函数的富集因子。最佳评分函数用于了解配体蛋白质与四种蛋白质的最常见化合物的相互作用。此外,我们对 Tb-PR 和利什曼原虫主要蝶啶还原酶 (Lm-PR) 的活性位点进行了 3D 结构比较。我们描述了 Tb-PR 和 Lm-PR 之间的关键结构差异,可用于针对这两种人类寄生虫的合理药物设计。

结论:结果表明,仅仅依靠重新对接和交叉对接实验进行文库虚拟筛选是不够的,结果可能会产生误导。因此,有人建议在大规模筛选之前进行小规模虚拟筛选。

更新日期:2020-11-09
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