title: Plasmin regulation through allosteric, sulfated, small molecules.
abstract: Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%-100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design.
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA. alhoranir@vcu.edu.
authors.forename: Rami A
authors.initials: RA
authors.lastname: Al-Horani
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA. rkaruturi@vcu.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Karuturi
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA. d.t.white17696@spartans.nsu.edu.
authors.forename: Domonique T
authors.initials: DT
authors.lastname: White
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA. urdesai@vcu.edu.
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D015951:Factor Xa / Q000378:metabolism; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007700:Kinetics; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015842:Serine Proteinase Inhibitors; D054852:Small Molecule Libraries; D013431:Sulfates; D015951:Factor Xa; D005341:Fibrinolysin