First steps in the direction of synthetic,allosteric, direct inhibitors of thrombin and factor Xa |
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| Authors: | Jenson Verghese Aiye Liang Preet Pal Singh Sidhu Michael Hindle Qibing Zhou Umesh R. Desai |
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| Affiliation: | 1. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States;2. Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA, United States;3. Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, United States;4. Department of Chemistry, Virginia Commonwealth University, Richmond, VA, United States |
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| Abstract: | Designing non-saccharide functional mimics of heparin is a major challenge. In this work, a library of small, aromatic molecules based on the sulfated DHP scaffold was synthesized and screened against thrombin and factor Xa. The results reveal that (i) selected monomeric benzofuran derivatives inhibit the two enzymes, albeit weakly; (ii) the two enzymes recognize different structural features in the benzofurans studied suggesting significant selectivity of recognition; and (iii) the mechanism of inhibition is allosteric. The molecules represent the first allosteric small molecule inhibitors of the two enzymes. |
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