Designing allosteric regulators of thrombin. Exosite 2 features multiple subsites that can be targeted by sulfated small molecules for inducing inhibition.
Research article published in Journal of medicinal chemistry (2013)
Abstract
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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
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.
Por qué esto importa para la hirudoterapia
Este estudio de diseño de fármacos sintetizó pequeñas moléculas de bencofurano sulfatado dirigidas al exositio 2 de la trombina e identificó un trímero (9a) aproximadamente diez veces más potente que los dímeros anteriores, con datos de Michaelis-Menten y barrido de alanina que respaldan un mecanismo alostérico y un sitio de reconocimiento distinto del exositio 2 (un defecto de potencia en Arg233). Se conecta con la hirudoterapia a través de su uso experimental de un péptido de hirudin como ligando del exositio 1 en estudios de competencia, ilustrando cómo el anticoagulante de sanguijuela hirudin sirve como herramienta molecular y punto de referencia en la investigación moderna de inhibidores de la trombina. Se trata de química medicinal in vitro sobre compuestos sintéticos, no de un estudio de terapia con sanguijuelas ni de una investigación clínica, por lo que su relevancia para ASH es mecanicista y contextual en lugar de una evidencia de beneficio terapéutico.
Citación
Designing allosteric regulators of thrombin. Exosite 2 features multiple subsites that can be targeted by sulfated small molecules for inducing inhibition.
Sidhu PS et al. · Journal of medicinal chemistry, 2013
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Añadido a la biblioteca ASH: May 28, 2026 · Última actualización del sitio: June 18, 2026