Synthesis of kojic acid derivatives as secondary binding site probes of d-amino acid oxidase

Raje, Mithun; Hin, Niyada; Duvall, Bridget; Ferraris, Dana; Berry, James F.; Thomas, Ajit G.; Alt, Jesse; Rojas, Camilo; Slusher, Barbara S.; Tsukamoto, Takashi

doi:10.1016/j.bmcl.2013.04.062

Cited by 22 publications

(27 citation statements)

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“…Pyrrole, quinoline and kojic acid derivatives that have previously been reported as h-DAAO inhibitors (Table 1) [13,14,33] were docked into the binding pocket of the h-DAAO monomer. The results revealed that most of the pyrrole derivatives (compounds 1 -23; Table 1) have a conserved binding mode (Figure 9(a)).…”

Section: Molecular Dockingmentioning

confidence: 99%

“…A total of 69 compounds (Table 1), previously reported as inhibitors of h-DAAO, were selected from the literature. [13,14,33] These inhibitors were docked into the binding pocket of h-DAAO using the GOLD4.0 program. [34,35] Docking parameters were first optimised by re-docking 3HQ into the binding pocket of h-DAAO to reproduce the binding mode of 3HQ determined by X-ray crystallography (PDB code: 3G3E).…”

Section: Molecular Dockingmentioning

confidence: 99%

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Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Wichapong

Nueangaudom

Pianwanit

et al. 2014

Molecular Simulation

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Schizophrenia is a mental illness; most affected people live in developing countries, and neither appropriate treatment nor commercial drugs are currently available. One possibility is to inhibit human-D-amino acid oxidase (h-DAAO). In this study, molecular dynamic simulations of the monomer, dimer and tetramer forms of h-DAAO complexed with the inhibitor 3-hydroxyquinolin-2(1H)-one(2) were performed. Seven residues, Leu51, Gln53, Leu215, Tyr228, Ile230, Arg283 and Gly313, were identified as essential for interacting with the inhibitor. Molecular docking of h-DAAO with pyrrole, quinoline and kojic acid derivatives, representing 69 known or potential h-DAAO inhibitors, was also performed. The results indicated that the activity of the inhibitor can be improved by modifying the compounds to have a substituent group capable of interacting with the side chain of Tyr228. Van der Waals interactions of the inhibitor with the hydrophobic pocket of h-DAAO and electrostatic interactions or H-bonds with Arg283 and Gly313 were important elements in determining the efficiency of the inhibitor. These results provide information on the interaction between h-DAAO and its inhibitors at the molecular level and can aid in the design of novel inhibitors against h-DAAO for new drug development in the treatment of schizophrenia.

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Section: Molecular Dockingmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Wichapong

Nueangaudom

Pianwanit

et al. 2014

Molecular Simulation

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“…This class of compounds, in which a substituted O-phenyl derivative was connected to kojic acid by a 2-atom linker, showed an IC 50 in the range of hundreds of nM (Table 3 ). Docking analysis of compound 19 to the active site of different experimental structures of hDAAO supported the hypothesis that the phenylthiomethyl group of the inhibitor is bound in the subpocket created by the conformational change of Tyr224 (Raje et al, 2013 ). The same research group identified a series of inhibitors with a similar steric hindrance [6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione derivates and 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives], but possessing a lower IC 50 (corresponding to 30 nM for compound 21 , the best one).…”

Section: Inhibitors Of Human Daaomentioning

confidence: 78%

“…Different research groups took advantage of the additional interactions of the ligand with the residues located at the entrance of the active site to design novel third-generation inhibitors. The first example of compounds that exploit this different mode of interaction with hDAAO are the kojic acid derivatives (e.g., compound 19 ) (Raje et al, 2013 ). This class of compounds, in which a substituted O-phenyl derivative was connected to kojic acid by a 2-atom linker, showed an IC 50 in the range of hundreds of nM (Table 3 ).…”

Section: Inhibitors Of Human Daaomentioning

confidence: 99%

Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase

Molla

2017

Front. Mol. Biosci.

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D-amino acid oxidase (DAAO) catalyzes the oxidative deamination of several neutral D-amino acids and is the enzyme mainly responsible (together with serine racemase) for degrading D-serine (D-Ser) in the central nervous system of mammals. This D-amino acid, which binds the coagonist site of the N-methyl-D-aspartate receptor, is thus a key neuromodulator of glutamatergic neurotransmission. Altered D-Ser metabolism results in several pathological conditions (e.g., amylotrophic lateral sclerosis or schizophrenia, SZ) for which effective “broad spectrum” pharmaceutical drugs are not yet available. In particular, the correlation between reduced D-Ser concentration and SZ led to a renaissance of biochemical interest in human DAAO (hDAAO). In the last 10 years, public and corporate research laboratories undertook huge efforts to study the structural, enzymatic, and physiological properties of the human flavoenzyme and to identify novel effective inhibitors which, acting as pharmaceutical drugs, could decrease hDAAO activity, thus restoring the physiological concentration of D-Ser. Although, none of the identified hDAAO inhibitors has reached the market yet, from a biochemical point of view, these compounds turned out to be invaluable for gaining a detailed understanding of the structure/function relationships at the molecular level in the mammalian DAAO, in particular of the interaction between ligand and the enzyme. This detailed knowledge, together with several recent studies concerning the interaction of the human enzyme with other protein regulative partners, its subcellular localization, and in vivo degradation, contributed to gaining comprehensive knowledge of the structure, function, and physiopathological role of this important human enzyme.

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“…4 For example, our group exploited this secondary binding site using kojic acid derivatives represented by compound 1 . 5 Similarly, a group at Astellas reported potent DAAO inhibitors including 2a–b based on a 4-hydroxypyridazin-3(2 H )-one scaffold with a phenethyl group extending to the secondary binding site. 6 2-Substituted 6-hydroxy-1,2,4-triazine-3,5(2 H ,4 H )-diones such as 3 exhibited not only potent DAAO inhibitory activity but also improved metabolic stability compared to 1–2 in liver microsomes.…”

mentioning

confidence: 99%

d-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

Hin

Duvall

Berry

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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A series of 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives were designed and synthesized as a new class of D-amino acid oxidase (DAAO) inhibitors. Some of the newly synthesized derivatives showed potent inhibitory activity against human DAAO with IC50 values in the nanomolar range. Among them, 6-hydroxy-3-phenethyl-1,2,4-triazin-5(2H)-one 6b and 3-((6-fluoronaphthalen-2-yl)methylthio)-6-hydroxy-1,2,4-triazin-5(2H)-one 6m were found to be metabolically stable in mouse liver microsomes. In addition, compound 6b was found to be orally available in mice and able to enhance plasma D-serine levels following its co-administration with D-serine compared to the oral administration of D-serine alone.

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Synthesis of kojic acid derivatives as secondary binding site probes of d-amino acid oxidase

Cited by 22 publications

References 15 publications

Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Molecular dynamics simulation, binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase

d-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

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