Design of drug-like hepsin inhibitors against prostate cancer and kidney stones
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 wor...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-07-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383519309566 |
| _version_ | 1818975419439775744 |
|---|---|
| author | Vincent Blay Mu-Chun Li Sunita P. Ho Mashall L. Stoller Hsing-Pang Hsieh Douglas R. Houston |
| author_facet | Vincent Blay Mu-Chun Li Sunita P. Ho Mashall L. Stoller Hsing-Pang Hsieh Douglas R. Houston |
| author_sort | Vincent Blay |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T15:55:39Z |
| format | Article |
| id | doaj.art-4fe19fde6bc74f4eb38af2e253e2255d |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-20T15:55:39Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-4fe19fde6bc74f4eb38af2e253e2255d2022-12-21T19:34:28ZengElsevierActa Pharmaceutica Sinica B2211-38352020-07-0110713091320Design of drug-like hepsin inhibitors against prostate cancer and kidney stonesVincent Blay0Mu-Chun Li1Sunita P. Ho2Mashall L. Stoller3Hsing-Pang Hsieh4Douglas R. Houston5Division 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; Corresponding author. Tel.: +1 415 5142818.Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan 350, ChinaDivision 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, USADivision 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, USAInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan 350, ChinaUniversity of Edinburgh, Institute of Quantitative Biology, Biochemistry and Biotechnology, Edinburgh, Scotland, EH9 3BF, UKHepsin, 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.http://www.sciencedirect.com/science/article/pii/S2211383519309566Virtual screeningDockingLibraryHepsinTamm-Horsfall proteinBiomineralization |
| spellingShingle | Vincent Blay Mu-Chun Li Sunita P. Ho Mashall L. Stoller Hsing-Pang Hsieh Douglas R. Houston Design of drug-like hepsin inhibitors against prostate cancer and kidney stones Acta Pharmaceutica Sinica B Virtual screening Docking Library Hepsin Tamm-Horsfall protein Biomineralization |
| title | Design of drug-like hepsin inhibitors against prostate cancer and kidney stones |
| title_full | Design of drug-like hepsin inhibitors against prostate cancer and kidney stones |
| title_fullStr | Design of drug-like hepsin inhibitors against prostate cancer and kidney stones |
| title_full_unstemmed | Design of drug-like hepsin inhibitors against prostate cancer and kidney stones |
| title_short | Design of drug-like hepsin inhibitors against prostate cancer and kidney stones |
| title_sort | design of drug like hepsin inhibitors against prostate cancer and kidney stones |
| topic | Virtual screening Docking Library Hepsin Tamm-Horsfall protein Biomineralization |
| url | http://www.sciencedirect.com/science/article/pii/S2211383519309566 |
| work_keys_str_mv | AT vincentblay designofdruglikehepsininhibitorsagainstprostatecancerandkidneystones AT muchunli designofdruglikehepsininhibitorsagainstprostatecancerandkidneystones AT sunitapho designofdruglikehepsininhibitorsagainstprostatecancerandkidneystones AT mashalllstoller designofdruglikehepsininhibitorsagainstprostatecancerandkidneystones AT hsingpanghsieh designofdruglikehepsininhibitorsagainstprostatecancerandkidneystones AT douglasrhouston designofdruglikehepsininhibitorsagainstprostatecancerandkidneystones |