Small molecule inhibitors of mesotrypsin from a structurebased docking screen

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 (CID22956468), 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 (K1) of 3.6±0.3 μM. 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.

Original languageEnglish (US)
Article numbere0176694
JournalPLoS One
Volume12
Issue number5
DOIs
StatePublished - May 1 2017

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Diminazene
diminazene
crystal structure
Crystal structure
Trypsin
trypsin
Molecules
Protein Isoforms
Pharmaceutical Databases
United States Food and Drug Administration
Biological Products
active sites
Free energy
Tumors
Catalytic Domain
Up-Regulation
Throughput
Availability
Databases
Pharmacology

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Small molecule inhibitors of mesotrypsin from a structurebased docking screen. / Kayode, Olumide; Huang, Zunnan; Soares, Alexei S.; Caulfield, Thomas; Dong, Zigang; Bode, Ann M.; Radisky, Evette S.

In: PLoS One, Vol. 12, No. 5, e0176694, 01.05.2017.

Research output: Contribution to journalArticle

Kayode, Olumide ; Huang, Zunnan ; Soares, Alexei S. ; Caulfield, Thomas ; Dong, Zigang ; Bode, Ann M. ; Radisky, Evette S. / Small molecule inhibitors of mesotrypsin from a structurebased docking screen. In: PLoS One. 2017 ; Vol. 12, No. 5.
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