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Understanding Dermatan Sulfate-Heparin Cofactor II Interaction through Virtual Library Screening
Arjun Raghuraman1, Philip D Mosier, Umesh R Desai
1Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23298-0540.
ACS Medicinal Chemistry Letters
|September 14, 2010
Summary
Dermatan sulfate interacts with heparin cofactor II to prevent blood clots. Computational screening identified a novel binding mode, aiding the design of new antithrombotic drugs.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Chemistry
Background:
- Dermatan sulfate, a glycosaminoglycan, and heparin cofactor II, a serpin, are crucial for antithrombotic response.
- The molecular details of their interaction are not well understood.
Purpose of the Study:
- To investigate the molecular interaction between dermatan sulfate and heparin cofactor II.
- To identify potential binding modes using computational methods.
Main Methods:
- Genetic algorithm-based combinatorial virtual library screening.
- Computational analysis of dermatan sulfate hexasaccharide topologies.
- Analysis of binding site interactions within heparin cofactor II.
Main Results:
- Out of 192 possible hexasaccharide topologies, only 16 met high-specificity criteria.
- 13 of these topologies were predicted to bind to heparin cofactor II's heparin-binding site.
- A novel binding mode was identified, with a ~60° angle to helix D, consistent with experimental data.
Conclusions:
- The identified binding mode supports thrombin ternary complexation via a template mechanism.
- This study facilitates the design of novel allosteric agonists of heparin cofactor II.
- The findings pave the way for developing new antithrombotic agents.
