title: First steps in the direction of synthetic, allosteric, direct inhibitors of thrombin and factor Xa.
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.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States.
authors.forename: Jenson
authors.initials: J
authors.lastname: Verghese
authors.forename: Aiye
authors.initials: A
authors.lastname: Liang
authors.forename: Preet Pal Singh
authors.initials: PP
authors.lastname: Sidhu
authors.forename: Michael
authors.initials: M
authors.lastname: Hindle
authors.forename: Qibing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000495:Allosteric Site; D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry*; D006493:Heparin / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000925:Anticoagulants; D001572:Benzofurans; D011108:Polymers; D006493:Heparin; D013917:Thrombin; D015951:Factor Xa; C105430:benzofuran