A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin |
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| Authors: | Daniel K. Afosah Stephen Verespy Rami A. Al-Horani Rio S. Boothello Rajesh Karuturi Umesh R. Desai |
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| Affiliation: | 1. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA;2. Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA;3. Department of Chemistry, Virginia Commonwealth University, Richmond, VA, USA;4. Division of Basic Pharmaceutical Sciences, Xavier University, New Orleans, LA, USA |
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| Abstract: | Despite the development of promising direct oral anticoagulants, which are all orthosteric inhibitors, a sizable number of patients suffer from bleeding complications. We have hypothesized that allosterism based on the heparin-binding exosites presents a major opportunity to induce sub-maximal inhibition of coagulation proteases, thereby avoiding/reducing bleeding risk. We present the design of a group of sulfated benzofuran dimers that display heparin-binding site-dependent partial allosteric inhibition of thrombin against fibrinogen (ΔY?=?55–75%), the first time that a small molecule (MW??
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| Keywords: | Allosteric inhibition Anticoagulants Thrombin Heparin-binding site Enzyme regulation |
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