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Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).

ABSTRACT: 3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.

SUBMITTER: Harrison ST

PROVIDER: S-EPMC4360154 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).

Harrison Scott T ST Poslusney Michael S MS Mulhearn James J JJ Zhao Zhijian Z Kett Nathan R NR Schubert Jeffrey W JW Melamed Jeffrey Y JY Allison Timothy J TJ Patel Sangita B SB Sanders John M JM Sharma Sujata S Smith Robert F RF Hall Dawn L DL Robinson Ronald G RG Sachs Nancy A NA Hutson Pete H PH Wolkenberg Scott E SE Barrow James C JC

ACS medicinal chemistry letters 20150126 3

3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures sugg ...[more]

PMID: 25815153

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Project description:Cynomolgus macaque COMT Val158Met encoded polymorphism

| PRJEB65031 | ENA

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Association between the Catechol O-methyltransferase (COMT) Val158met polymorphism and different dimensions of impulsivity.

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Inhibition of human catechol-O-methyltransferase (COMT)-mediated O-methylation of catechol estrogens by major polyphenolic components present in coffee.

Project description:In the present study, we investigated the inhibitory effect of three catechol-containing coffee polyphenols, chlorogenic acid, caffeic acid and caffeic acid phenethyl ester (CAPE), on the O-methylation of 2- and 4-hydroxyestradiol (2-OH-E(2) and 4-OH-E(2), respectively) catalyzed by the cytosolic catechol-O-methyltransferase (COMT) isolated from human liver and placenta. When human liver COMT was used as the enzyme, chlorogenic acid and caffeic acid each inhibited the O-methylation of 2-OH-E(2) in a concentration-dependent manner, with IC(50) values of 1.3-1.4 and 6.3-12.5 microM, respectively, and they also inhibited the O-methylation of 4-OH-E(2), with IC(50) values of 0.7-0.8 and 1.3-3.1 microM, respectively. Similar inhibition pattern was seen with human placental COMT preparation. CAPE had a comparable effect as caffeic acid for inhibiting the O-methylation of 2-OH-E(2), but it exerted a weaker inhibition of the O-methylation of 4-OH-E(2). Enzyme kinetic analyses showed that chlorogenic acid and caffeic acid inhibited the human liver and placental COMT-mediated O-methylation of catechol estrogens with a mixed mechanism of inhibition (competitive plus noncompetitive). Computational molecular modeling analysis showed that chlorogenic acid and caffeic acid can bind to human soluble COMT at the active site in a similar manner as the catechol estrogen substrates. Moreover, the binding energy values of these two coffee polyphenols are lower than that of catechol estrogens, which means that coffee polyphenols have higher binding affinity for the enzyme than the natural substrates. This computational finding agreed perfectly with our biochemical data.

| S-EPMC2674329 | biostudies-literature

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