Elucidating the specificity of non-heparin-based conformational activators of antithrombin for factor Xa inhibition

INTRODUCTION: Antithrombin, the principal inhibitor of coagulation proteases, requires allosteric activation by its physiological cofactor, heparin or heparin sulfate to achieve physiologically permissible rates. This forms the basis of heparin's use as a clinical anticoagulant. However, heparin therapy is beset with severe complications, giving rise to the need to search new non-heparin activators of antithrombin, devoid of these complications and with favorable safety profiles. MATERIALS AND METHODS: We chose some representative organic compounds that have been shown to be involved in coagulation modulation by affecting antithrombin and applied a blind docking protocol to find the binding energy and interactions of the modified (sulfated) versus unmodified organic scaffolds. RESULTS AND CONCLUSION: Increased sulfation plays a key role in shifting the specificity of organic compounds like quercetin, diosmin, rutin, mangiferin, isomangostin, Trapezifolixanthone and benzofuran towards the heparin binding site (HBS). However, in hesperetin and tetrahydroisoquinoline, sulfation shifts the specificity away from HBS. We have further tried to elucidate changes in the binding affinity of quercetin on account of gradual increase in the number of hydroxyl groups being substituted by sulfate groups. The results show gradual increase in binding energy with increase in sulfation. A theoretical screening approach is an ideal mechanism to predict lead molecules as activators of antithrombin and in determining the specificity for antithrombin.