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

• 作者: Douglas R.Houston Hsing-Pang Hsieh Mashall L.Stoller Mu-Chun Li Sunita P.Ho Vincent Blav
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2020,（7）
• 所属期刊栏目: Original Articles
• 页码范围: 1309-1320
• 页数: 12页
• 语种: 英文

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 AD-MET 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.