Design of drug-like hepsin inhibitors against prostate cancer and kidney stones

Vincent Blay, Mu Chun Li, Sunita P. Ho, Mashall L. Stoller, Hsing Pang Hsieh, Douglas R. Houston

研究成果: Article同行評審

1 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)1309-1320
頁數12
期刊Acta Pharmaceutica Sinica B
10
發行號7
DOIs
出版狀態Published - 2020 七月

All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)

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