A β-tryptase inhibitor with a tropanylamide scaffold to improve in vitro stability and to lower hERG channel binding affinity

Liang, Guyan; Choi-Sledeski, Yong Mi; Shum, Patrick; Chen, Xin; Poli, Gregory; Kumar, Vasant; Minnich, Anne; Wang, Qingping; Tsay, Joseph; Sides, Keith; Kang, Jiesheng; Zhang, Ying

doi:10.1016/j.bmcl.2011.12.127

Cited by 16 publications

(27 citation statements)

References 19 publications

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“…23,25,52 In order to find out the vital role heparin plays in the bII-tryptase monomer, molecular docking method was used and the complex of 4-mer heparin-bII-tryptase monomer was thus obtained. Moreover, the MM-GB/SA calculations for the Hep system has a similar tendency with the experiment results 10 which may indicate that bII-tryptase monomer is indeed in its active form when 4-mer heparin was present. We have investigated the atomic-level structural variations between the monomer structure of human bII-tryptase with and without 4-mer heparin to understand the molecular origin for the stabilization of protein structure by heparin.…”

Section: Discussionsupporting

confidence: 72%

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Heparin makes differences: a molecular dynamics simulation study on the human βII-tryptase monomer

et al. 2015

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Human β-tryptase, an enzyme with trypsin-like activity in mast cells, is an important target for the treatment of inflammatory and allergy related diseases. Heparin has been inferred to play a vital role in the stabilization of the tryptase structure and the maintenance of its active form. Up to now, the structure-function relationship between heparin and the βII-tryptase monomer has not been studied with atomic resolution due to the lack of a complex structure of tryptase and heparin. To this end, the exact effect of heparin bonding to the βII-tryptase monomer structure has been investigated using molecular docking and molecular dynamics (MD) simulation. The MD simulation results combined with MM-GB/SA calculations showed that heparin stabilized the β-tryptase structure mainly through salt bridge interaction. The averaged noncovalent interaction (aNCI) method was employed for the visualization of nonbonding interactions. A crucial loop, which is located in the core region of βII-tryptase monomer structure, has been found. Arg188 and Asp189 from this loop act as a salt bridge intermediary between 4-mer heparin and 0GX. The observation of a salt bridge between Asp189 and P1 groups of 0GX confirms the supposed interaction between these two groups. These two residues have been proved to be responsible for the direction of the P1 group of 0GX. Our study revealed that how heparin affected the activity of the human βII-tryptase monomer (hBTM) through salt bridge interactions. The knowledge of heparin binding characteristics and the key residue contributions in this study may enlighten further the inhibitor design of this enzyme and may also improve our understanding of inflammatory and allergy related diseases.

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Section: Discussionsupporting

confidence: 72%

“…The crystal structure of human bII-tryptase complex with its inhibitor 0GX was retrieved from the RCSB Brookhaven Protein Data Bank (PDB entry: 3V7T), 10 which was served as the starting structure for the following docking calculations. The chemical structure of inhibitor 0GX is shown in Fig.…”

Section: Initial Structuresmentioning

confidence: 99%

Heparin makes differences: a molecular dynamics simulation study on the human βII-tryptase monomer

et al. 2015

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“…A, surface rendering of the ␤II-tryptase monomer showing the active site residues in magenta, the Cys 220 -Cys 248 disulfide bond in yellow, and an inhibitor bound in the active site in orange (Protein Data Bank identifier 3V7T) (62). B, close-up of the active site.…”

Section: Figurementioning

confidence: 99%

Allosteric Control of βII-Tryptase by a Redox Active Disulfide Bond

Cook

McNeil

Hogg

2013

Journal of Biological Chemistry

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Background:The S1A serine proteases function in many biological processes and contain a conserved disulfide bond near the active site.Results: This disulfide in the S1A mast cell protease, ␤II-tryptase, exists in oxidized and reduced states in the enzyme, which influences the specificity and efficiency of the enzyme. Conclusion: ␤II-Tryptase is regulated by an allosteric disulfide bond. Significance: Other S1A proteases are likely similarly regulated.

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“…Polyvalent binding increases the affinity and specificity of interactions between molecules [67], as confirmed in the current study. Bivalent inhibitors of tryptase that engage two pharmacophoric binding sites spanning approximately 34 Å have demonstrated more than a 1000-fold increase in selectivity and affinity and have shown efficacy in early clinical studies [41, 68, 69]. However, these molecules possess high molecular weights, are double-charged and the physicochemical properties of these molecules produce poor drug-like performances [24, 69].…”

Section: Discussionmentioning

confidence: 99%

A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human β-Tryptase

et al. 2018

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β-Tryptase is released from mast cells upon degranulation in response to allergic and inflammatory stimuli. Human tryptase is a homotetrameric serine protease with 4 identical active sites directed toward a central pore. These active sites present an optimized scenario for the rational design of bivalent inhibitors, which bridge 2 adjacent active sites. Using (3-[1-acylpiperidin-4-yl]phenyl)methanamine as the pharmacophoric core and a disiloxane linker to span 2 active sites we have successfully produced a novel bivalent tryptase inhibitor, compound 1a, with a comparable profile to previously described inhibitors. Pharmacological properties of compound 1a were studied in a range of in vitro enzymic and cellular screening assays, and in vivo xenograft models. This non-peptide inhibitor of tryptase demonstrated superior activity (IC₅₀ at 100 pmol/L tryptase = 1.82 nmol/L) compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and 1a demonstrated good oral bioavailability and efficacy in HMC-1 xenograft models. Furthermore, compound 1a demonstrated extremely slow off rates and high selectivity against-related proteases. This highly potent, orally bioavailable and selective inhibitor of human tryptase will be an invaluable tool in future studies to explore the therapeutic potential of attenuating the activity of this elusive target.

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A β-tryptase inhibitor with a tropanylamide scaffold to improve in vitro stability and to lower hERG channel binding affinity

Cited by 16 publications

References 19 publications

Heparin makes differences: a molecular dynamics simulation study on the human βII-tryptase monomer

Heparin makes differences: a molecular dynamics simulation study on the human βII-tryptase monomer

Allosteric Control of βII-Tryptase by a Redox Active Disulfide Bond

A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human β-Tryptase

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