Understanding Dermatan Sulfate-Heparin Cofactor II Interaction through Virtual Library Screening.
ACS Med Chem Lett
; 1(6): 281-285, 2010 Sep 09.
Article
in En
| MEDLINE
| ID: mdl-20835364
ABSTRACT
Dermatan sulfate, an important member of the glycosaminoglycan family, interacts with heparin cofactor II, a member of the serpin family of proteins, to modulate antithrombotic response. Yet, the nature of this interaction remains poorly understood at a molecular level. We report the genetic algorithm-based combinatorial virtual library screening study of a natural, high-affinity dermatan sulfate hexasaccharide with heparin cofactor II. Of the 192 topologies possible for the hexasaccharide, only 16 satisfied the "high-specificity" criteria used in computational study. Of these, 13 topologies were predicted to bind in the heparin-binding site of heparin cofactor II at a â¼60° angle to helix D, a novel binding mode. This new binding geometry satisfies all known solution and mutagenesis data and supports thrombin ternary complexation through a template mechanism. The study is expected to facilitate the design of allosteric agonists of heparin cofactor II as antithrombotic agents.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Language:
En
Journal:
ACS Med Chem Lett
Year:
2010
Document type:
Article