当前位置: X-MOL 学术Acta Pharm. Sin. B › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Design of drug-like hepsin inhibitors against prostate cancer and kidney stones.
Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2019-09-28 , DOI: 10.1016/j.apsb.2019.09.008
Vincent Blay,Mu-Chun Li,Sunita P Ho,Mashall L Stoller,Hsing-Pang Hsieh,Douglas R Houston

Hepsin, a transmembrane serine protease abundant in renal endothelial cells, is a promising therapeutic target against several cancers, particularly prostate cancer. It is involved in the release and polymerization of uromodulin in the urine, which plays a role in kidney stone formation. In this work, we design new potential hepsin inhibitors for high activity, improved specificity towards hepsin, and promising ADMET properties. The ligands were developed in silico through a novel hierarchical pipeline. This pipeline explicitly accounts for off-target binding to the related serine proteases matriptase and HGFA (human hepatocyte growth factor activator). We completed the pipeline incorporating ADMET properties of the candidate inhibitors into custom multi-objective optimization functions. The ligands designed show excellent prospects for targeting hepsin via the blood stream and the urine and thus enable key experimental studies. The computational pipeline proposed is remarkably cost-efficient and can be easily adapted for designing inhibitors against new drug targets.



中文翻译:

抗前列腺癌和肾结石的药物样肝素抑制剂的设计。

肝素,一种在肾内皮细胞中丰富的跨膜丝氨酸蛋白酶,是针对几种癌症,特别是前列腺癌的有希望的治疗靶标。它参与尿液中尿调节素的释放和聚合,这在肾结石的形成中起作用。在这项工作中,我们设计了新的潜在的肝素抑制剂,具有较高的活性,提高了对肝素的特异性,并有望实现ADMET特性。配体是在计算机上开发通过新颖的分层管道。这条管道明确说明了脱靶结合相关丝氨酸蛋白酶matriptase和HGFA(人类肝细胞生长因子激活剂)。我们完成了将候选抑制剂的ADMET属性整合到自定义多目标优化函数中的流程。设计的配体显示出通过血流和尿液靶向肝素的极好的前景,因此可以进行关键的实验研究。所提出的计算流程具有很高的成本效益,并且可以轻松地用于设计针对新药物靶标的抑制剂。

更新日期:2019-09-28
down
wechat
bug