Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP
The great interest in studying the structure of human purine nucleoside phosphorylase (<i>h</i>PNP) and the continued search for effective inhibitors is due to the importance of the enzyme as a target in the therapy of T-cell proliferative diseases. In addition, <i>h</i>PNP i...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/3/928 |
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| author | Anastasia Khandazhinskaya Ilja Fateev Barbara Eletskaya Anna Maslova Irina Konstantinova Katherine Seley-Radtke Sergey Kochetkov Elena Matyugina |
| author_facet | Anastasia Khandazhinskaya Ilja Fateev Barbara Eletskaya Anna Maslova Irina Konstantinova Katherine Seley-Radtke Sergey Kochetkov Elena Matyugina |
| author_sort | Anastasia Khandazhinskaya |
| collection | DOAJ |
| description | The great interest in studying the structure of human purine nucleoside phosphorylase (<i>h</i>PNP) and the continued search for effective inhibitors is due to the importance of the enzyme as a target in the therapy of T-cell proliferative diseases. In addition, <i>h</i>PNP inhibitors are used in organ transplant surgeries to provide immunodeficiency during and after the procedure. Previously, we showed that members of the well-known fleximer class of nucleosides are substrates of <i>E. coli</i> PNP. Fleximers have great promise as they have exhibited significant biological activity against a number of viruses of pandemic concern. Herein, we describe the synthesis and inhibition studies of a series of new fleximer compounds against <i>h</i>PNP and discuss their possible binding mode with the enzyme. At a concentration of 2 mM for the flex-7-deazapurines <b>1–4</b>, a decrease in enzymatic activity by more than 50% was observed. 4-Amino-5-(1H-pyrrol-3-yl)pyridine <b>2</b> was the best inhibitor, with a Ki = 0.70 mM. Docking experiments have shown that ligand <b>2</b> is localized in the selected binding pocket Glu201, Asn243 and Phe200. The ability of the pyridine and pyrrole fragments to undergo rotation around the C–C bond allows for multiple binding modes in the active site of <i>h</i>PNP, which could provide several plausible bioactive conformations. |
| first_indexed | 2024-03-11T09:34:39Z |
| format | Article |
| id | doaj.art-b65b17ea6c56490da3ee0b1081f4459f |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T09:34:39Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b65b17ea6c56490da3ee0b1081f4459f2023-11-16T17:25:07ZengMDPI AGMolecules1420-30492023-01-0128392810.3390/molecules28030928Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNPAnastasia Khandazhinskaya0Ilja Fateev1Barbara Eletskaya2Anna Maslova3Irina Konstantinova4Katherine Seley-Radtke5Sergey Kochetkov6Elena Matyugina7Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaDepartment of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USAEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaThe great interest in studying the structure of human purine nucleoside phosphorylase (<i>h</i>PNP) and the continued search for effective inhibitors is due to the importance of the enzyme as a target in the therapy of T-cell proliferative diseases. In addition, <i>h</i>PNP inhibitors are used in organ transplant surgeries to provide immunodeficiency during and after the procedure. Previously, we showed that members of the well-known fleximer class of nucleosides are substrates of <i>E. coli</i> PNP. Fleximers have great promise as they have exhibited significant biological activity against a number of viruses of pandemic concern. Herein, we describe the synthesis and inhibition studies of a series of new fleximer compounds against <i>h</i>PNP and discuss their possible binding mode with the enzyme. At a concentration of 2 mM for the flex-7-deazapurines <b>1–4</b>, a decrease in enzymatic activity by more than 50% was observed. 4-Amino-5-(1H-pyrrol-3-yl)pyridine <b>2</b> was the best inhibitor, with a Ki = 0.70 mM. Docking experiments have shown that ligand <b>2</b> is localized in the selected binding pocket Glu201, Asn243 and Phe200. The ability of the pyridine and pyrrole fragments to undergo rotation around the C–C bond allows for multiple binding modes in the active site of <i>h</i>PNP, which could provide several plausible bioactive conformations.https://www.mdpi.com/1420-3049/28/3/928aza/deazapurinesfleximer inhibitorhuman purine nucleoside phosphorylase |
| spellingShingle | Anastasia Khandazhinskaya Ilja Fateev Barbara Eletskaya Anna Maslova Irina Konstantinova Katherine Seley-Radtke Sergey Kochetkov Elena Matyugina Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP Molecules aza/deazapurines fleximer inhibitor human purine nucleoside phosphorylase |
| title | Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP |
| title_full | Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP |
| title_fullStr | Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP |
| title_full_unstemmed | Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP |
| title_short | Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP |
| title_sort | design and synthesis of new modified flexible purine bases as potential inhibitors of human pnp |
| topic | aza/deazapurines fleximer inhibitor human purine nucleoside phosphorylase |
| url | https://www.mdpi.com/1420-3049/28/3/928 |
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