Application of drug discovery software to the identification of heparin-binding sites on protein surfaces: a computational survey of the 4-helix cytokines

• Published in: Molecular simulation Vol. 34; no. 4; pp. 481 - 489
• Main Authors: Mulloy, Barbara, Forster, M.J.
• Format: Journal Article
• Language: English
• Published: Taylor & Francis Group 01-04-2008; Taylor & Francis
• Subjects: cytokine; docking; drug discovery; heparan sulfate; heparin; Physical Sciences
• ISSN: 0892-7022; 1029-0435
• DOI: 10.1080/08927020701784754

Heparin, best known as a potent anticoagulant, also interacts with many other proteins for which the natural ligand is heparan sulfate (HS). The hope that HS would display specific sequences which would bind selectively to each of these proteins has not been fulfilled, but this may be at least in part due to the relationship between HS sequence and 3D structure. The example of FGF-1 is used to demonstrate that many different sequences can give rise to the 3D patterns of charge, which form binding motifs for proteins. Partly because of this redundancy in sequence-to-structure relationship, the application of conventional high-throughput drug discovery methods for the development of heparin or heparan based therapeutic agents is not yet practicable. However, it is possible to adapt systematic docking calculations to work in a moderately high throughput manner to screen protein structures from the Protein Data Bank (PDB) for predicted heparin-binding sites. A survey of protein structures in the Structural Classification of Protiens (SCOP) superfamily of 4-helical cytokines is presented.