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Title: Small molecule inhibitors of mesotrypsin from a structure-based docking screen

Abstract

PRSS3/mesotrypsin is an atypical isoform of trypsin, the upregulation of which has been implicated in promoting tumor progression. To date there are no mesotrypsin-selective pharmacological inhibitors which could serve as tools for deciphering the pathological role of this enzyme, and could potentially form the basis for novel therapeutic strategies targeting mesotrypsin. A virtual screen of the Natural Product Database (NPD) and Food and Drug Administration (FDA) approved Drug Database was conducted by high-throughput molecular docking utilizing crystal structures of mesotrypsin. Twelve high-scoring compounds were selected for testing based on lowest free energy docking scores, interaction with key mesotrypsin active site residues, and commercial availability. Diminazene (C1D22956468), along with two similar compounds presenting the bis-benzamidine substructure, was validated as a competitive inhibitor of mesotrypsin and other human trypsin isoforms. Diminazene is the most potent small molecule inhibitor of mesotrypsin reported to date with an inhibitory constant (K i) of 3.6±0.3 pM. Diminazene was subsequently co-crystalized with mesotrypsin and the crystal structure was solved and refined to 1.25 Å resolution. This high resolution crystal structure can now offer a foundation for structure-guided efforts to develop novel and potentially more selective mesotrypsin inhibitors based on similar molecular substructures.

Authors:
 [1];  [2];  [3];  [4];  [2];  [2]; ORCiD logo [1]
  1. Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL (United States). Department of Cancer Biology
  2. University of Minnesota, Austin, MN (United States). The Hormel Institute
  3. Brookhaven National Lab. (BNL), Upton, NY (United States). Photon Sciences Directorate
  4. Mayo Clinic College of Medicine, Jacksonville, FL (United States). Department of Neuroscience
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH)
OSTI Identifier:
1430883
Report Number(s):
BNL-203390-2018-JAAM
Journal ID: ISSN 1932-6203
Grant/Contract Number:  
SC0012704
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 12; Journal Issue: 5; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; mesotrypsin; trypsin; serine protease; protease inhibitor; drug discovery; structure-based docking; in-silico screening; virtual screening; crystal structure; x-ray crystallography

Citation Formats

Kayode, Olumide, Huang, Zunnan, Soares, Alexei S., Caulfield, Thomas R., Dong, Zigang, Bode, Ann M., and Radisky, Evette S. Small molecule inhibitors of mesotrypsin from a structure-based docking screen. United States: N. p., 2017. Web. doi:10.1371/journal.pone.0176694.
Kayode, Olumide, Huang, Zunnan, Soares, Alexei S., Caulfield, Thomas R., Dong, Zigang, Bode, Ann M., & Radisky, Evette S. Small molecule inhibitors of mesotrypsin from a structure-based docking screen. United States. doi:10.1371/journal.pone.0176694.
Kayode, Olumide, Huang, Zunnan, Soares, Alexei S., Caulfield, Thomas R., Dong, Zigang, Bode, Ann M., and Radisky, Evette S. Tue . "Small molecule inhibitors of mesotrypsin from a structure-based docking screen". United States. doi:10.1371/journal.pone.0176694. https://www.osti.gov/servlets/purl/1430883.
@article{osti_1430883,
title = {Small molecule inhibitors of mesotrypsin from a structure-based docking screen},
author = {Kayode, Olumide and Huang, Zunnan and Soares, Alexei S. and Caulfield, Thomas R. and Dong, Zigang and Bode, Ann M. and Radisky, Evette S.},
abstractNote = {PRSS3/mesotrypsin is an atypical isoform of trypsin, the upregulation of which has been implicated in promoting tumor progression. To date there are no mesotrypsin-selective pharmacological inhibitors which could serve as tools for deciphering the pathological role of this enzyme, and could potentially form the basis for novel therapeutic strategies targeting mesotrypsin. A virtual screen of the Natural Product Database (NPD) and Food and Drug Administration (FDA) approved Drug Database was conducted by high-throughput molecular docking utilizing crystal structures of mesotrypsin. Twelve high-scoring compounds were selected for testing based on lowest free energy docking scores, interaction with key mesotrypsin active site residues, and commercial availability. Diminazene (C1D22956468), along with two similar compounds presenting the bis-benzamidine substructure, was validated as a competitive inhibitor of mesotrypsin and other human trypsin isoforms. Diminazene is the most potent small molecule inhibitor of mesotrypsin reported to date with an inhibitory constant (Ki) of 3.6±0.3 pM. Diminazene was subsequently co-crystalized with mesotrypsin and the crystal structure was solved and refined to 1.25 Å resolution. This high resolution crystal structure can now offer a foundation for structure-guided efforts to develop novel and potentially more selective mesotrypsin inhibitors based on similar molecular substructures.},
doi = {10.1371/journal.pone.0176694},
journal = {PLoS ONE},
number = 5,
volume = 12,
place = {United States},
year = {Tue May 02 00:00:00 EDT 2017},
month = {Tue May 02 00:00:00 EDT 2017}
}

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Works referenced in this record:

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158