Abstract

The β-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, Ki = 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 C3-alkyl-linked -D-glucose fragments, stronger in fIIa (15.5 kJ•mol-1) than in fXa (2.8 kJ•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.

Autore Pugliese

• Altomare Cosimo Damiano , Colucci Mario , De Candia Modesto

Tutti gli autori

• ALTOMARE C.D.;COLUCCI M.;DE CANDIA M.

Titolo volume/Rivista

Non Disponibile

Anno di pubblicazione

2014

ISSN

0022-2623

ISBN

Non Disponibile

Numero di citazioni Wos

3

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

2

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

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Codici ASJC

Non Disponibile