对重要的肿瘤学靶点 PRL3 中可能存在的药物口袋进行硅学鉴定

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Grace M. Bennett, Julia Starczewski, Mark Vincent C. dela Cerna
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引用次数: 0

摘要

蛋白酪氨酸磷酸酶(PTP)已成为癌症等以异常磷酸化为特征的疾病的靶点。再生肝 3 磷酸酶 PRL3 的活性与多种致癌和转移途径有关,尤其是在乳腺癌、卵巢癌、结直肠癌和血癌中。然而,直接靶向 PRL3 的小分子药物的开发一直面临挑战。部分原因是缺乏有关 PRL3 如何与其抑制剂相互作用的结构信息。本文采用计算方法,通过评估 PRL3 的可药性来弥补这一不足。特别是使用基于网络的口袋预测工具 DoGSite3 和 FTMap,利用蛋白质数据库中现有的 PRL3 结构来确定结合口袋。此外,还通过分子动力学模拟探针进行了可药性评估,以验证这些结果并预测已确定口袋的结合强度。虽然发现了几个可药用的口袋,但鉴于其体积和深度,封闭构象中的口袋更有前景。这两个口袋位于活性位点环的侧面,与之前论文中分子对接预测的口袋大致对应。值得注意的是,可药性模拟预测这些位点可能存在纳摩尔级的低亲和力抑制剂,这意味着有可能为 PRL3 找出高效力的小分子抑制剂。这里发现的推定口袋可用于高通量虚拟筛选,以进一步加速针对 PRL3 的药物发现和 PRL3 定向疗法的开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In silico identification of putative druggable pockets in PRL3, a significant oncology target

Protein tyrosine phosphatases (PTP) have emerged as targets in diseases characterized by aberrant phosphorylations such as cancers. The activity of the phosphatase of regenerating liver 3, PRL3, has been linked to several oncogenic and metastatic pathways, particularly in breast, ovarian, colorectal, and blood cancers. Development of small molecules that directly target PRL3, however, has been challenging. This is partly due to the lack of structural information on how PRL3 interacts with its inhibitors. Here, computational methods are used to bridge this gap by evaluating the druggability of PRL3. In particular, web-based pocket prediction tools, DoGSite3 and FTMap, were used to identify binding pockets using structures of PRL3 currently available in the Protein Data Bank. Druggability assessment by molecular dynamics simulations with probes was also performed to validate these results and to predict the strength of binding in the identified pockets. While several druggable pockets were identified, those in the closed conformation show more promise given their volume and depth. These two pockets flank the active site loops and roughly correspond to pockets predicted by molecular docking in previous papers. Notably, druggability simulations predict the possibility of low nanomolar affinity inhibitors in these sites implying the potential to identify highly potent small molecule inhibitors for PRL3. Putative pockets identified here can be leveraged for high-throughput virtual screening to further accelerate the drug discovery against PRL3 and development of PRL3-directed therapeutics.

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来源期刊
Biochemistry and Biophysics Reports
Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics
CiteScore
4.60
自引率
0.00%
发文量
191
审稿时长
59 days
期刊介绍: Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.
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