Exploring new non-sugar sulfated molecules as activators of antithrombin.
New non-sugar, small, sulfated molecules, based on our de novo rationally designed activator (-)-epicatechin sulfate (ECS), were investigated to bind and activate antithrombin, an inhibitor of plasma coagulation enzyme factor Xa. For the activators studied, the equilibrium dissociation constant (K(D)) of the interaction with plasma antithrombin varies nearly 53-fold, with the highest affinity of 1.8 microM observed for morin sulfate, while the acceleration in factor Xa inhibition varies 2.6-fold. The results demonstrate that antithrombin binding and activation is a common property of these small sulfated molecules and suggests plausible directions for designing more potent activators.
Gunnarsson
Gunnar T
GT
Department of Medicinal Chemistry, Virginia Commonwealth University, 410 N. 12th Street, PO Box 980540, Richmond, VA 23298, USA.
Desai
Umesh R
UR
D000990:Antithrombin III / Q000819:agonists*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D065427:Factor Xa Inhibitors; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D013329:Structure-Activity Relationship; D013463:Sulfuric Acid Esters / Q000737:chemistry / Q000494:pharmacology*
D065427:Factor Xa Inhibitors; D005419:Flavonoids; D013463:Sulfuric Acid Esters; C452422:epicatechin sulfate; D002392:Catechin; D000990:Antithrombin III