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

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外文摘要：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.

外文关键词：

Virtual screeningDockingLibraryHepsinTamm-Horsfall proteinBiomineralization

作者：

Vincent Blav、Mu-Chun Li、Sunita P.Ho、Mashall L.Stoller、Hsing-Pang Hsieh、Douglas R.Houston

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作者单位：

Division of Biomaterials and Bioengineering, School of Dentistry, University of California San Francisco, San Francisco, CA 94143, USA

Department of Urology, School of Medicine, University of California San Francisco, San Francisco, CA 94143,USA

Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan 350, China

University of Edinburgh, Institute of Quantitative Biology, Biochemistry and Biotechnology, Edinburgh, Scotland,EH9 3BF, UK

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基金：

authors thank Optibrium Ltdfor permission to include results from StarDropVBlay thanks the Scottish Funding Council and the

项目编号：

出版年：

2020

药学学报(英文版)

CSTPCDCSCDSCI

ISSN：

年,卷(期)：2020.10(7)

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