title: Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site.
abstract: To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the Vmax of substrate hydrolysis without influencing the KM. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs.
authors: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors: Rajesh
authors: R
authors: Karuturi
authors: Rami A
authors: RA
authors: Al-Horani
authors: Shrenik C
authors: SC
authors: Mehta
authors: David
authors: D
authors: Gailani
authors: Umesh R
authors: UR
authors: Desai
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D040761:Biomimetic Materials / Q000494:pharmacology; D020134:Catalytic Domain; D055808:Drug Discovery; D015945:Factor XIa / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000737:chemistry; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology*; D013431:Sulfates / Q000737:chemistry
chemical_list: D006025:Glycosaminoglycans; D011480:Protease Inhibitors; D052999:Quinazolinones; D013431:Sulfates; D006493:Heparin; D015945:Factor XIa