http://www.cnr.it/ontology/cnr/individuo/prodotto/ID305456
How a beta-D-Glucoside Side Chain Enhances Binding Affinity to Thrombin of Inhibitors Bearing 2-Chlorothiophene as P1 Moiety: Crystallography, Fragment Deconstruction Study, and Evaluation of Antithrombotic Properties (Articolo in rivista)
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- How a beta-D-Glucoside Side Chain Enhances Binding Affinity to Thrombin of Inhibitors Bearing 2-Chlorothiophene as P1 Moiety: Crystallography, Fragment Deconstruction Study, and Evaluation of Antithrombotic Properties (Articolo in rivista) (literal)
- Anno
- 2014-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1021/jm5010754 (literal)
- Alternative label
Belviso, Benny D.; Caliandro, Rocco; de Candia, Modesto; Zaetta, Giorgia; Lopopolo, Gianfranco; Incampo, Francesca; Colucci, Mario; Altomare, Cosimo D. (2014)
How a beta-D-Glucoside Side Chain Enhances Binding Affinity to Thrombin of Inhibitors Bearing 2-Chlorothiophene as P1 Moiety: Crystallography, Fragment Deconstruction Study, and Evaluation of Antithrombotic Properties
in Journal of medicinal chemistry
(literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Belviso, Benny D.; Caliandro, Rocco; de Candia, Modesto; Zaetta, Giorgia; Lopopolo, Gianfranco; Incampo, Francesca; Colucci, Mario; Altomare, Cosimo D. (literal)
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- Consiglio Nazionale delle Ricerche (CNR); University of Bari; University of Bari (literal)
- Titolo
- How a beta-D-Glucoside Side Chain Enhances Binding Affinity to Thrombin of Inhibitors Bearing 2-Chlorothiophene as P1 Moiety: Crystallography, Fragment Deconstruction Study, and Evaluation of Antithrombotic Properties (literal)
- Abstract
- The beta-d-glucose-containing compound 3, bearing 2-chlorothiophene and 1-isopropylpiperidine moieties as binders of the S1 and S4 pockets, respectively, proved to be potent competitive inhibitor of factor Xa (fXa, K-i = 0.090 nM) and thrombin (fIIa, Ki = 100 nM). The potency of 3 increases, over the parent compound 1, against fIIa (110-fold), much more than against fXa (7-fold). Experimental deconstruction of 3 into smaller fragments revealed a binding cooperativity of the P3/P4 and propylene-linked beta-d-glucose fragments, stronger in fIIa (15.5 kJ center dot mol(-1)) than in fXa (2.8 kJ center dot mol(-1)). The crystal structure of human fIIa in complex with 3 revealed a binding mode including a strong H-bond network between the glucose O1', O3', and O5' and two critical residues, namely R221a and K224, belonging to the Na+-binding site which may allosterically perturb the specificity sites. The potential of 3 as antithrombotic agent was supported by its ability to inhibit thrombin generation and to stimulate fibrinolysis at submicromolar concentration. (literal)
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