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

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

Research output: Contribution to journalArticlepeer-review

Abstract

Hepsin, a transmembrane serine protease abundant in renal endothelial cells, is a promising therapeutic target againstseveral 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 proteasesmatriptase and HGFA. 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.
Original languageEnglish
Pages (from-to)1309-1320
JournalActa Pharmaceutica Sinica B
Volume10
Issue number7
Early online date28 Sep 2019
DOIs
Publication statusE-pub ahead of print - 28 Sep 2019

Keywords

  • virtual screening
  • docking
  • library
  • hepsin
  • tamm-horsfall protein
  • biomineralization

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