title: On designing non-saccharide, allosteric activators of antithrombin.
abstract: Antithrombin, a plasma glycoprotein serpin, requires conformational activation by heparin to induce an anticoagulant effect, which is mediated through accelerated factor Xa inhibition. Heparin, a highly charged polymer and an allosteric activator of the serpin, is associated with major adverse effects. To design better, but radically different activators of antithrombin from heparin, we utilized a pharmacophore-based approach. A tetrahydroisoquinoline-based scaffold was designed to mimic four critical anionic groups of the key trisaccharide DEF constituting the sequence-specific pentasaccharide DEFGH in heparin. Activator IAS(5) containing 5,6-disulfated tetrahydroisoquinoline and 3,4,5-trisulfated phenyl rings was found to bind antithrombin at pH 7.4 with an affinity comparable to the reference trisaccharide DEF. IAS(5) activated the inhibitor nearly 30-fold, nearly 2- to 3-fold higher than our first generation flavanoid-based designs. This work advances the concept of antithrombin activation through non-saccharide, organic molecules and pinpoints a direction for the design of more potent molecules.
authors.affiliation: Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, 410 N. 12th Street, PO Box 980540, Richmond, VA 23298-0540, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Raghuraman
authors.forename: Aiye
authors.initials: A
authors.lastname: Liang
authors.forename: Chandravel
authors.initials: C
authors.lastname: Krishnasamy
authors.forename: Trish
authors.initials: T
authors.lastname: Lauck
authors.forename: Gunnar T
authors.initials: GT
authors.lastname: Gunnarsson
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006493:Heparin / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000991:Antithrombins; D065427:Factor Xa Inhibitors; D044005:Tetrahydroisoquinolines; D006493:Heparin