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

Kayode, Olumide; Huang, Zunnan; Soares, Alexei S.; Caulfield, Thomas R.; Dong, Zigang; Bode, Ann M.; Radisky, Evette S.

doi:10.1371/journal.pone.0176694

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

Journal Article · Tue May 02 00:00:00 EDT 2017 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0176694· OSTI ID:1430883

Kayode, Olumide ^[1]; Huang, Zunnan ^[2]; Soares, Alexei S. ^[3]; Caulfield, Thomas R. ^[4]; Dong, Zigang ^[2]; Bode, Ann M. ^[2];

^[1]

Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL (United States). Department of Cancer Biology
University of Minnesota, Austin, MN (United States). The Hormel Institute
Brookhaven National Lab. (BNL), Upton, NY (United States). Photon Sciences Directorate
Mayo Clinic College of Medicine, Jacksonville, FL (United States). Department of Neuroscience

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.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)

Grant/Contract Number:: SC0012704

OSTI ID:: 1430883

Report Number(s):: BNL-203390-2018-JAAM

Journal Information:: PLoS ONE, Vol. 12, Issue 5; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 14 works

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Proteases: Pivot Points in Functional Proteomics Verhamme, Ingrid M.; Leonard, Sarah E.; Perkins, Ray C. Functional Proteomics https://doi.org/10.1007/978-1-4939-8814-3_20	book	October 2018

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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

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

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