Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site.

Karuturi R, Al-Horani RA, Mehta SC, Gailani D, Desai UR
J Med Chem. 2013 56 (6): 2415-28

PMID: 23451707 · PMCID: PMC3625964 · DOI:10.1021/jm301757v

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.

MeSH Terms (12)

Allosteric Regulation Biomimetic Materials Catalytic Domain Drug Discovery Factor XIa Glycosaminoglycans Heparin Humans Hydrophobic and Hydrophilic Interactions Protease Inhibitors Quinazolinones Sulfates

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