Hydropathic interaction analyses of small organic activators binding to antithrombin.
Recently we designed the first small organic ligands, sulfated flavanoids and flavonoids, that act as activators of antithrombin for accelerated inhibition of factor Xa, a key proteinase of the coagulation cascade [Gunnarsson and Desai, Bioorg. Med. Chem. Lett. (2003) 13:579]. To better understand the binding properties of these activators at a molecular level, we have utilized computerized hydropathic interaction (HINT) analyses of the sulfated molecules interacting in two plausible electropositive regions, the pentasaccharide- and extended heparin-binding sites, of antithrombin in its native and activated forms. HINT analyses indicate favorable multi-point interactions of the activators in both binding sites of the two forms of antithrombin. Yet, HINT predicts better interaction of most activators, except for (-)-catechin sulfate, with the activated form of antithrombin than with the native form supporting the observation in solution that these molecules function as activators of the inhibitor. Further, whereas (+)-catechin sulfate recognized the activated form of antithrombin better in both the pentasaccharide- and extended heparin- binding sites, the native form was better recognized by (-)-catechin sulfate, thus explaining its weaker binding and activation potential in solution. A reasonable linear correlation between the overall HINT score and the solution free energy of binding of the sulfated activators was evident. This investigation indicates that HINT is a useful tool in understanding interactions of antithrombin with small sulfated organic ligands at a molecular level, has some good predictive properties, and is likely to be useful for rational design purposes.
Gunnarsson
Gunnar T
GT
Department of Medicinal Chemistry, Virginia Commonwealth University, 410N. 12th Street, PO Box 980540, Richmond, VA 23298, USA.
Desai
Umesh R
UR
D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000991:Antithrombins / Q000737:chemistry*; D001665:Binding Sites; D019281:Dimerization; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013455:Sulfur / Q000737:chemistry; D014867:Water / Q000737:chemistry
D000596:Amino Acids; D000991:Antithrombins; D005419:Flavonoids; D008024:Ligands; D014867:Water; D013455:Sulfur