Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase

Kirkland, Thomas A.; Adler, Marc; Bauman, John G.; Chen, Ming; Haeggström, Jesper Z.; King, Beverly; Kochanny, Monica J.; Liang, Amy; Mendoza, Lisa M.; Phillips, Gary B.; Thunnissen, Marjolein M.G.M.; Trinh, Lan; Whitlow, Marc; Ye, Bin; Ye, Hong; Parkinson, John F.; Guilford, William H.

doi:10.1016/j.bmc.2008.03.042

Cited by 35 publications

(40 citation statements)

References 34 publications

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“…Inasmuch as LTA4H catalyzes the final and committed step in the biosynthesis of the potent chemotactic agent LTB 4 , this enzyme has been an interesting target for development of anti-inflammatory drugs. Thus, several highly potent and selective inhibitors have been developed within academia as well as industry (13)(14)(15)(16). However, none of these compounds have met the expectations and demonstrated clinical usefulness.…”

Section: Resultsmentioning

confidence: 99%

Binding of Pro-Gly-Pro at the active site of leukotriene A ₄ hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor

Stsiapanava

Olsson

Wan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Leukotriene (LT) A 4 hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc metalloenzyme that catalyzes biosynthesis of the proinflammatory mediator, LTB 4 , implicated in chronic inflammatory diseases. Recently, the chemotactic tripeptide Pro-Gly-Pro was identified as the enzyme’s endogenous peptidase substrate. Pro-Gly-Pro is cleaved and inactivated by LTA4H, suggesting that LTA4H plays a role in both the initiation and the resolution phase of inflammation. Here, we defined the binding and cleavage mechanism for Pro-Gly-Pro at the active site of LTA4H. Moreover, we designed a small molecule that selectively blocks synthesis of LTB 4 , although sparing the peptidase activity for inactivation of Pro-Gly-Pro, thus representing a novel type of LTA4H inhibitor that may pave the way for development of better treatments of inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Binding of Pro-Gly-Pro at the active site of leukotriene A ₄ hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor

Stsiapanava

Olsson

Wan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Molecular docking results from Paz et al [232] provided an interaction model of LTA4 with LTA4H in excellent correlation with the experimental data: the substrate fits in the active site of the enzyme arranging its functional groups according to the reaction mechanism proposed by several authors [233,234,235,236]. Both species of LTA4, protonated and deprotonated, bind to the same site with proper orientation of the key groups for the enzymatic reaction.…”

Section: Influence Of Ph and Protonation States In Docking Studiesmentioning

confidence: 72%

Some Critical Aspects of Molecular Interactions Between Drugs and Receptors

Yunta¹

2014

AJMO

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Protonation states are sometimes crucial for free energy calculations to predict binding ability of molecules to receptors, a main subject for drug design. This mini-review seeks to identify the importance of knowing the influence of pH in such studies to better achieve correct predictions for drug candidates. Protonation states, for both proteins and drugs, need to be considered in docking studies although they have been usually neglected.

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“…Amino acid derived arylamides are a class of carboxamides, widely used in the synthesis of polymers, dendrimers, peptidomimetics, inhibitors and as cell signaling molecules (Vemparala et al 2006;Yin et al 2006;Vinogradov 2005;Meegalla et al 2008;Kirkland et al 2008;Hang et al 2006). They are used as substrates in chromogenic, fluorogenic and amperogenic enzymatic assays.…”

Section: Introductionmentioning

confidence: 99%

An Efficient and Epimerization Free Synthesis of C-Terminal Arylamides Derived from α-Amino Acids and Peptide Acids via T3P Activation

Madhu

NageswaraRao

Narendra

et al. 2014

Int J Pept Res Ther

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Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase

Cited by 35 publications

References 34 publications

Binding of Pro-Gly-Pro at the active site of leukotriene A ₄ hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor

Binding of Pro-Gly-Pro at the active site of leukotriene A ₄ hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor

Some Critical Aspects of Molecular Interactions Between Drugs and Receptors

An Efficient and Epimerization Free Synthesis of C-Terminal Arylamides Derived from α-Amino Acids and Peptide Acids via T3P Activation

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Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase

Cited by 35 publications

References 34 publications

Binding of Pro-Gly-Pro at the active site of leukotriene A 4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor

Binding of Pro-Gly-Pro at the active site of leukotriene A 4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor

Some Critical Aspects of Molecular Interactions Between Drugs and Receptors

An Efficient and Epimerization Free Synthesis of C-Terminal Arylamides Derived from α-Amino Acids and Peptide Acids via T3P Activation

Contact Info

Product

Resources

About

Binding of Pro-Gly-Pro at the active site of leukotriene A ₄ hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor

Binding of Pro-Gly-Pro at the active site of leukotriene A ₄ hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor