title: Hydropathic interaction analyses of small organic activators binding to antithrombin.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 410N. 12th Street, PO Box 980540, Richmond, VA 23298, USA.
authors.forename: Gunnar T
authors.initials: GT
authors.lastname: Gunnarsson
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: 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
chemical_list: D000596:Amino Acids; D000991:Antithrombins; D005419:Flavonoids; D008024:Ligands; D014867:Water; D013455:Sulfur