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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 (hPNP) 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, hPNP inhibitors are used in organ transplant...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9921493/ https://www.ncbi.nlm.nih.gov/pubmed/36770593 http://dx.doi.org/10.3390/molecules28030928 |
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author | Khandazhinskaya, Anastasia Fateev, Ilja Eletskaya, Barbara Maslova, Anna Konstantinova, Irina Seley-Radtke, Katherine Kochetkov, Sergey Matyugina, Elena |
author_facet | Khandazhinskaya, Anastasia Fateev, Ilja Eletskaya, Barbara Maslova, Anna Konstantinova, Irina Seley-Radtke, Katherine Kochetkov, Sergey Matyugina, Elena |
author_sort | Khandazhinskaya, Anastasia |
collection | PubMed |
description | The great interest in studying the structure of human purine nucleoside phosphorylase (hPNP) 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, hPNP 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 E. coli 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 hPNP and discuss their possible binding mode with the enzyme. At a concentration of 2 mM for the flex-7-deazapurines 1–4, a decrease in enzymatic activity by more than 50% was observed. 4-Amino-5-(1H-pyrrol-3-yl)pyridine 2 was the best inhibitor, with a Ki = 0.70 mM. Docking experiments have shown that ligand 2 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 hPNP, which could provide several plausible bioactive conformations. |
format | Online Article Text |
id | pubmed-9921493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99214932023-02-12 Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP Khandazhinskaya, Anastasia Fateev, Ilja Eletskaya, Barbara Maslova, Anna Konstantinova, Irina Seley-Radtke, Katherine Kochetkov, Sergey Matyugina, Elena Molecules Article The great interest in studying the structure of human purine nucleoside phosphorylase (hPNP) 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, hPNP 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 E. coli 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 hPNP and discuss their possible binding mode with the enzyme. At a concentration of 2 mM for the flex-7-deazapurines 1–4, a decrease in enzymatic activity by more than 50% was observed. 4-Amino-5-(1H-pyrrol-3-yl)pyridine 2 was the best inhibitor, with a Ki = 0.70 mM. Docking experiments have shown that ligand 2 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 hPNP, which could provide several plausible bioactive conformations. MDPI 2023-01-17 /pmc/articles/PMC9921493/ /pubmed/36770593 http://dx.doi.org/10.3390/molecules28030928 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Khandazhinskaya, Anastasia Fateev, Ilja Eletskaya, Barbara Maslova, Anna Konstantinova, Irina Seley-Radtke, Katherine Kochetkov, Sergey Matyugina, Elena Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9921493/ https://www.ncbi.nlm.nih.gov/pubmed/36770593 http://dx.doi.org/10.3390/molecules28030928 |
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