Antithrombin conformational modulation by D-myo-inositol 3, 4, 5, 6-tetrakisphosphate (TMI), a novel scaffold for the development of antithrombotic agents. Issue 15 (18th November 2018)

• Record Type: Journal Article
• Authors: Arantes, Pablo Ricardo; Pérez-Sánchez, Horacio; Verli, Hugo
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 36:Issue 15(2018)
• Page Start: 4045
• Page End: 4056
• Publication Date: 2018-11-18
• Subjects: antithrombin -- TMI -- molecular dynamics -- molecular modeling -- bioinformatics; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2017.1407259
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract : Antithrombin (AT) is a serpin that inhibits mainly thrombin and fXa after being activated by binding to glycosaminoglycans as heparin and heparan sulfate. Upon binding, the native AT conformation, relatively inactive as a protease inhibitor, is converted to an activated form. Recently, a new compound, named TMI, was discovered in our group with nanomolar affinity to antithrombin, and shown to be able to induce a partial activation of antithrombin. As TMI represents an original scaffold for structural optimizations aiming the development of new antithrombotic drugs, the present work demonstrated, through a series of molecular dynamics simulations, that TMI is able to modulate AT reactive center loop flexibility similarly to what is observed to heparin, as well as exposing AT P1 residue, Arg393. These results represent the first atomic level indication of AT conformational activation by TMI, and may offer a predictive basis for future studies aiming TMI structural optimization.