First steps in the direction of synthetic, allosteric, direct inhibitors of thrombin and factor Xa.
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.
Verghese
Jenson
J
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States.
Liang
Aiye
A
Sidhu
Preet Pal Singh
PP
Hindle
Michael
M
Zhou
Qibing
Q
Desai
Umesh R
UR
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*
D000925:Anticoagulants; D001572:Benzofurans; D011108:Polymers; D006493:Heparin; D013917:Thrombin; D015951:Factor Xa; C105430:benzofuran