Designing Allosteric Regulators of Thrombin. Exosite 2 Features Multiple Subsites That Can Be Targeted by Sulfated Small Molecules for Inducing Inhibition
We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. Among these, trimer 9a was found to be nearly 10-fold more potent than the first generation molecules. Michaelis-Menten studies indicated an allosteric mechanism of inhibition. Competitive studies using a hirudin peptide (exosite 1 ligand) and unfractionated heparin, heparin octasaccharide, and γ'-fibrinogen peptide (exosite 2 ligands) demonstrated exosite 2 recognition in a manner different from that of the parent dimers. Alanine scanning mutagenesis of 12 Arg/Lys residues of exosite 2 revealed a defect in 9a potency for Arg233Ala thrombin only confirming the major difference in site of recognition between the two structurally related sulfated benzofurans. The results suggest that multiple avenues are available within exosite 2 for inducing thrombin inhibition.
Pharmacology, Toxicology and Pharmaceutical Science
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4%
Other
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Unknown
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Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 18 January 2016.
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#7,453,479
of 22,786,691 outputs
Outputs from Journal of Medicinal Chemistry
#12,752
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Outputs of similar age
#65,764
of 196,989 outputs
Outputs of similar age from Journal of Medicinal Chemistry
#93
of 144 outputs
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