Design of drug-like hepsin inhibitors against prostate cancer and kidney stones.
10.1016/j.apsb.2019.09.008
- Author:
Vincent BLAY
1
;
Mu-Chun LI
2
;
Sunita P HO
1
;
Mashall L STOLLER
1
;
Hsing-Pang HSIEH
2
;
Douglas R HOUSTON
3
Author Information
1. Division of Biomaterials and Bioengineering, School of Dentistry, University of California San Francisco, San Francisco, CA 94143, USA.
2. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan 350, China.
3. University of Edinburgh, Institute of Quantitative Biology, Biochemistry and Biotechnology, Edinburgh, Scotland, EH9 3BF, UK.
- Publication Type:Journal Article
- Keywords:
Biomineralization;
Docking;
Hepsin;
Library;
Tamm-Horsfall protein;
Virtual screening
- From:
Acta Pharmaceutica Sinica B
2020;10(7):1309-1320
- CountryChina
- Language:English
-
Abstract:
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 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 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.
