title: Allosteric inhibition of human factor XIa: discovery of monosulfated benzofurans as a class of promising inhibitors.
abstract: Factor XIa (fXIa) is being recognized as a prime target for developing safer anticoagulants. To discover synthetic, small, allosteric inhibitors of fXIa, we screened an in-house, unique library of 65 molecules displaying many distinct scaffolds and varying levels of sulfation. Of these, monosulfated benzofurans were the only group of molecules found to inhibit fXIa (∼100% efficacy) and led to the identification of monosulfated trimer 24 (IC50 0.82 μM) as the most potent inhibitor. Michaelis-Menten kinetics studies revealed a classic noncompetitive mechanism of action for 24. Although monosulfated, the inhibitors did not compete with unfractionated heparin alluding to a novel site of interaction. Fluorescence quenching studies indicated that trimer 24 induces major conformational changes in the active site of fXIa. Docking studies identified a site near Lys255 on the A3 domain of fXIa as the most probable site of binding for 24. Factor XIa devoid of the A3 domain displayed a major defect in the inhibition potency of 24 supporting the docking prediction. Our work presents the sulfated benzofuran scaffold as a promising framework to develop allosteric fXIa inhibitors that likely function through the A3 domain.
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University , Richmond, Virginia 23219, United States.
authors.forename: Malaika D
authors.initials: MD
authors.lastname: Argade
authors.forename: Akul Y
authors.initials: AY
authors.lastname: Mehta
authors.forename: Aurijit
authors.initials: A
authors.lastname: Sarkar
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000495:Allosteric Site; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D055808:Drug Discovery; D015945:Factor XIa / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D062105:Molecular Docking Simulation
chemical_list: D000925:Anticoagulants; D001572:Benzofurans; D015945:Factor XIa