Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors
Most of the known inhibitors of D-amino acid oxidase (DAAO) are small polar molecules recognized by the active site of the enzyme. More recently a new class of DAAO inhibitors has been disclosed that interacts with loop 218−224 at the top of the binding pocket. These compounds have a significantly l...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-01-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/24/2/290 |
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| author | Bence Szilágyi Csilla Hargitai Ádám A. Kelemen Anita Rácz György G. Ferenczy Balázs Volk György M. Keserű |
| author_facet | Bence Szilágyi Csilla Hargitai Ádám A. Kelemen Anita Rácz György G. Ferenczy Balázs Volk György M. Keserű |
| author_sort | Bence Szilágyi |
| collection | DOAJ |
| description | Most of the known inhibitors of D-amino acid oxidase (DAAO) are small polar molecules recognized by the active site of the enzyme. More recently a new class of DAAO inhibitors has been disclosed that interacts with loop 218−224 at the top of the binding pocket. These compounds have a significantly larger size and more beneficial physicochemical properties than most reported DAAO inhibitors, however, their structure-activity relationship is poorly explored. Here we report the synthesis and evaluation of this type of DAAO inhibitors that open the lid over the active site of DAAO. In order to collect relevant SAR data we varied two distinct parts of the inhibitors. A systematic variation of the pendant aromatic substituents according to the Topliss scheme resulted in DAAO inhibitors with low nanomolar activity. The activity showed low sensitivity to the substituents investigated. The variation of the linker connecting the pendant aromatic moiety and the acidic headgroup revealed that the interactions of the linker with the enzyme were crucial for achieving significant inhibitory activity. Structures and activities were analyzed based on available X-ray structures of the complexes. Our findings might support the design of drug-like DAAO inhibitors with advantageous physicochemical properties and ADME profile. |
| first_indexed | 2024-04-12T18:33:30Z |
| format | Article |
| id | doaj.art-f10f017070194c2ea5f460e388e6ab09 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-12T18:33:30Z |
| publishDate | 2019-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f10f017070194c2ea5f460e388e6ab092022-12-22T03:21:00ZengMDPI AGMolecules1420-30492019-01-0124229010.3390/molecules24020290molecules24020290Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase InhibitorsBence Szilágyi0Csilla Hargitai1Ádám A. Kelemen2Anita Rácz3György G. Ferenczy4Balázs Volk5György M. Keserű6Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryDirectorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, H-1475 Budapest, HungaryMedicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryPlasma Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryMedicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryDirectorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, H-1475 Budapest, HungaryMedicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, HungaryMost of the known inhibitors of D-amino acid oxidase (DAAO) are small polar molecules recognized by the active site of the enzyme. More recently a new class of DAAO inhibitors has been disclosed that interacts with loop 218−224 at the top of the binding pocket. These compounds have a significantly larger size and more beneficial physicochemical properties than most reported DAAO inhibitors, however, their structure-activity relationship is poorly explored. Here we report the synthesis and evaluation of this type of DAAO inhibitors that open the lid over the active site of DAAO. In order to collect relevant SAR data we varied two distinct parts of the inhibitors. A systematic variation of the pendant aromatic substituents according to the Topliss scheme resulted in DAAO inhibitors with low nanomolar activity. The activity showed low sensitivity to the substituents investigated. The variation of the linker connecting the pendant aromatic moiety and the acidic headgroup revealed that the interactions of the linker with the enzyme were crucial for achieving significant inhibitory activity. Structures and activities were analyzed based on available X-ray structures of the complexes. Our findings might support the design of drug-like DAAO inhibitors with advantageous physicochemical properties and ADME profile.http://www.mdpi.com/1420-3049/24/2/290D-amino acid oxidase (DAAO)inhibitorlid-open conformationTopliss schemestructure-activity relationship |
| spellingShingle | Bence Szilágyi Csilla Hargitai Ádám A. Kelemen Anita Rácz György G. Ferenczy Balázs Volk György M. Keserű Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors Molecules D-amino acid oxidase (DAAO) inhibitor lid-open conformation Topliss scheme structure-activity relationship |
| title | Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors |
| title_full | Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors |
| title_fullStr | Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors |
| title_full_unstemmed | Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors |
| title_short | Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors |
| title_sort | synthesis and biochemical evaluation of lid open d amino acid oxidase inhibitors |
| topic | D-amino acid oxidase (DAAO) inhibitor lid-open conformation Topliss scheme structure-activity relationship |
| url | http://www.mdpi.com/1420-3049/24/2/290 |
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