Akul Y Mehta

Virginia Commonwealth University, Richmond, Virginia, United States

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Publications (7)27.01 Total impact

  • [show abstract] [hide abstract]
    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 kinetic 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.
    Journal of Medicinal Chemistry 03/2014; · 5.61 Impact Factor
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    ABSTRACT: Exosite 2 of human thrombin contributes to two opposing pathways, the anticoagulant pathway and the platelet aggregation pathway. We reasoned that an exosite 2-directed allosteric thrombin inhibitor should simultaneously induce anticoagulant as well as antiplatelet effects. To assess this, we synthesized SbO4L based on the sulfated tyrosine-containing sequence of GPIbalpha. SbO4L was synthesized in three simple steps in high yield and found to be a highly selective, direct inhibitor of thrombin. Michelis-Menten kinetic studies indicated a non-competitive mechanism of inhibition. Competitive inhibition studies suggested ideal competition with heparin and glycoprotein Ibalpha, as predicted. Studies with site-directed mutants of thrombin indicated that SbO4L binds to Arg233, Lys235 and Lys236 of exosite 2. SbO4L prevented thrombin-mediated platelet activation and aggregation as expected on the basis of competition with GPIbalpha. SbO4L presents a novel paradigm of simultaneous dual anticoagulant and antiplatelet effects achieved through the GPIbalpha binding site of thrombin.
    Journal of Medicinal Chemistry 03/2014; · 5.61 Impact Factor
  • Akul Y Mehta, Yingzi Jin, Umesh R Desai
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    ABSTRACT: Introduction: Thromboembolic incidences have increased nearly 33% in the past decade and directly affect nearly 0.5% of the population. Heparin, warfarin and current direct thrombin inhibitors (DTIs), the primary anticoagulants of choice, suffer from several drawbacks. Thus, the search for an antithrombotic devoid of adverse effect continues in earnest. Areas covered: Literature search covering PubMed, SciFinder(™) Scholar, Web of Knowledge, Espacenet, PatentScope and Google Patent Search was used to uncover > 35 patents describing new chemical entities and advances in DTI technologies. Our search uncovered considerable emphasis on the development of larger more complex molecules such as peptide-based inhibitors, prodrug derivatives, bivalent tryptophan zippers, triple action inhibitors and allosteric inhibitors. Advances in formulation technologies for clinically relevant DTIs have also been made. Expert opinion: Thrombin is a multifaceted, dynamic enzyme with both coagulant and anticoagulant functions. Newer DTIs are attempting to fine tune thrombin's activity by targeting allosteric sites or by site-specific targeting of clotting. The complexity of thrombin's functions is driving the design of complex anticoagulants. Advancements in formulations and production processes have attempted to make traditional DTIs more cost effective to produce. The literature reveals a trend to develop a thrombin 'modulator' rather than an 'inhibitor.'
    Expert Opinion on Therapeutic Patents 10/2013; · 3.53 Impact Factor
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    ABSTRACT: Direct inhibition of coagulation factor Xa (FXa) carries significant promise for developing effective and safe anticoagulants. Although a large number of FXa inhibitors have been studied, each can be classified as either possessing a highly flexible or a rigid core scaffold. We reasoned that an intermediate level of flexibility will provide high selectivity for FXa considering that its active site is less constrained in comparison to thrombin and more constrained as compared to trypsin. We studied several core scaffolds including 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid for direct FXa inhibition. Using a genetic algorithm-based docking and scoring approach, a promising candidate 23 was identified, synthesized, and found to inhibit FXa with a K(i) of 28 μM. Optimization of derivative 23 resulted in the design of a potent dicarboxamide 47, which displayed a K(i) of 135 nM. Dicarboxamide 47 displayed at least 1852-fold selectivity for FXa inhibition over other coagulation enzymes and doubled PT and aPTT of human plasma at 17.1 μM and 20.2 μM, respectively, which are comparable to those of clinically relevant agents. Dicarboxamide 47 is expected to serve as an excellent lead for further anticoagulant discovery.
    European journal of medicinal chemistry 06/2012; 54:771-83. · 3.27 Impact Factor
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    ABSTRACT: The serine protease thrombin plays multiple roles in many important physiological processes, especially coagulation, where it functions as both a pro- and anticoagulant. The polyanionic glycosaminoglycan heparin modulates thrombin's activity through binding at exosite II. Sucrose octasulfate (SOS) is often used as a surrogate for heparin, but it is not known whether it is an effective heparin mimic in its interaction with thrombin. We have characterized the interaction of SOS with thrombin in solution and determined a crystal structure of their complex. SOS binds thrombin with a K(d) of ~1.4 μM, comparable to that of the much larger polymeric heparin measured under the same conditions. Nonionic (hydrogen bonding) interactions make a larger contribution to thrombin binding of SOS than to heparin. SOS binding to exosite II inhibits thrombin's catalytic activity with high potency but with low efficacy. Analytical ultracentrifugation shows that bovine and human thrombins are monomers in solution in the presence of SOS, in contrast to their complexes with heparin, which are dimers. In the X-ray crystal structure, two molecules of SOS are bound nonequivalently to exosite II portions of a thrombin dimer, in contrast to the 1:2 stoichiometry of the heparin-thrombin complex, which has a different monomer association mode in the dimer. SOS and heparin binding to exosite II of thrombin differ on both chemical and structural levels and, perhaps most significantly, in thrombin inhibition. These differences may offer paths to the design of more potent exosite II binding, allosteric small molecules as modulators of thrombin function.
    Biochemistry 08/2011; 50(32):6973-82. · 3.38 Impact Factor
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    ABSTRACT: Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin. A sulfated benzofuran library of 15 sulfated monomers and 13 sulfated dimers with different charged, polar, and hydrophobic substituents was studied in this work. Synthesis of the sulfated benzofurans was achieved through a multiple step, highly branched strategy, which culminated with microwave-assisted chemical sulfation. Of the 28 potential inhibitors, 11 exhibited reasonable inhibition of human α-thrombin at pH 7.4. Structure-activity relationship analysis indicated that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. A tert-butyl 5-sulfated benzofuran derivative was found to be the most potent thrombin inhibitor with an IC(50) of 7.3 μM under physiologically relevant conditions. Michaelis-Menten studies showed an allosteric inhibition phenomenon. Plasma clotting assays indicate that the sulfated benzofurans prolong both the activated partial thromboplastin time and prothrombin time. Overall, this work puts forward sulfated benzofurans as the first small, synthetic molecules as powerful lead compounds for the design of a new class of allosteric inhibitors of thrombin.
    Journal of Medicinal Chemistry 06/2011; 54(15):5522-31. · 5.61 Impact Factor
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    ABSTRACT: Thrombotic disorders are among the leading causes of deaths in the US. Anticoagulants represent the mainstay for their treatment. Different mechanistic approaches have been exploited to deliver new anticoagulants, among which direct and indirect inhibition of factor Xa (fXa) of the coagulation cascade, carries a great promise for designing effective and safe anticoagulants. We utilized tetrahydroisoquinoline-3-carboxylic acid (THIQ3CA) to design potential orally bioavailable, direct fXa inhibitors. (3S)-THIQ3CA was used as core structure to generate a chem. library of 158 THIQ3CA-based dicarboxamides, which were computationally docked and scored into fXa active site. One particular hit with an IC50 of 56 μM was targeted for further studies. To design better molecules., a three-step scheme of amidation-deprotection-amidation was exploited to synthesize 60 related six-membered cyclic dicarboxamides. The dicarboxamides contained systematic modifications at 2- and 3- substituents as well as the core structure. Chromogenic substrate hydrolysis inhibition assay demonstrated a wide range of activity, from high μM to nM. The most potent dicarboxamide displayed fXa IC50 of 273 nM with greater than 1887-fold selectivity over other clotting proteases. It also demonstrated a selectivity index of 40- and 377-fold over chymotrypsin and trypsin, resp. This compound doubled aPTT and PT at 23.2 μM and 18.7 μM, resp., which are comparable to those of several agents currently in advanced clinical trials. Overall, rational design led to an increase in activity of the initial hit more than 200-fold while maintaining high selectivity over other serine proteases. The identified most potent dicarboxamide is expected to serve as an excellent lead for further anticoagulant discovery.
    63rd Southeastern Regional Meeting of the American Chemical Society; 01/2011