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| Main Authors: | , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
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European journal of medicinal chemistry
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40168911/ |
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| author | Ying, Ti-Ti Hu, Hao-Qiang Wu, Xiao-Wen Xu, Xu-Liang Lv, Jian Zhang, Shu-Ning Wang, Hong Hou, Wei Wei, Bin Rao, Guo-Wu |
| author_facet | Ying, Ti-Ti Hu, Hao-Qiang Wu, Xiao-Wen Xu, Xu-Liang Lv, Jian Zhang, Shu-Ning Wang, Hong Hou, Wei Wei, Bin Rao, Guo-Wu Ying, Ti-Ti Hu, Hao-Qiang Wu, Xiao-Wen Xu, Xu-Liang Lv, Jian Zhang, Shu-Ning Wang, Hong Hou, Wei Wei, Bin Rao, Guo-Wu |
| collection | PubMed - marine biology |
| contents | Optimized ebselen derivatives as novel potent Escherichia coli β-glucuronidase covalent allosteric inhibitors. Ying, Ti-Ti Hu, Hao-Qiang Wu, Xiao-Wen Xu, Xu-Liang Lv, Jian Zhang, Shu-Ning Wang, Hong Hou, Wei Wei, Bin Rao, Guo-Wu Escherichia coli Structure-Activity Relationship Organoselenium Compounds Glucuronidase Azoles Enzyme Inhibitors Isoindoles Molecular Structure Dose-Response Relationship, Drug Allosteric Regulation Molecular Docking Simulation Stilbenes Glycoproteins Gut microbial β-glucuronidase (GUS) plays a key role in metabolizing compounds and influencing disease and drug metabolism, highlighting the need for potent inhibitors to improve drug efficacy and intestinal health. To identify Escherichia coli β-glucuronidase (EcGUS) inhibitors, we designed and synthesized fifty 1,2-benzoselenazol-3-one (BSEA) derivatives using a bioisosterism strategy. Among these, twenty-five BSEA derivatives demonstrated greater inhibitory efficacy than the most potent known EcGUS inhibitor, amoxapine (AMX), with compound 49 showing the strongest activity, achieving an IC of 12.9 nM. Structure-inhibitory activity relationship analysis suggested that modifications such as adding benzene rings or nitrogenous heterocycles to the BSEA scaffold enhanced inhibitory activity, influenced by the type and position of substituents. The LC-MS analysis confirmed that compounds 31 and 49 covalently modify Cys197 in EcGUS, and additional covalent linkage of compound 49 was observed on Cys28 and Cys443. In addition, the jump dilution assays proved that compounds 31 was irreversible covalent inhibitors, and its kinetic parameter k/K were determined to be 21292.9 Ms. The compounds 49 was reversible covalent inhibitors and its apparent steady-state inhibition constant K∗ were determined to be 23.33 nM. Molecular docking predicted specific interactions, such as hydrogen bonds involving Se and the pyrazole NH of compound 49 with Cys28 and Cys449, which may contribute to its inhibitory action. This study reports the first discovery of covalent inhibitors for EcGUS, with optimized BSEA derivatives acting as novel allosteric covalent inhibitors, revealing structure-activity relationships and molecular determinants that establish their potential in drug development. |
| format | Artículo científico |
| id | pubmed_40168911 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | European journal of medicinal chemistry |
| record_format | pubmed |
| spellingShingle | Optimized ebselen derivatives as novel potent Escherichia coli β-glucuronidase covalent allosteric inhibitors. Ying, Ti-Ti Hu, Hao-Qiang Wu, Xiao-Wen Xu, Xu-Liang Lv, Jian Zhang, Shu-Ning Wang, Hong Hou, Wei Wei, Bin Rao, Guo-Wu Escherichia coli Structure-Activity Relationship Organoselenium Compounds Glucuronidase Azoles Enzyme Inhibitors Isoindoles Molecular Structure Dose-Response Relationship, Drug Allosteric Regulation Molecular Docking Simulation Stilbenes Glycoproteins Optimized ebselen derivatives as novel potent Escherichia coli β-glucuronidase covalent allosteric inhibitors. Ying, Ti-Ti Hu, Hao-Qiang Wu, Xiao-Wen Xu, Xu-Liang Lv, Jian Zhang, Shu-Ning Wang, Hong Hou, Wei Wei, Bin Rao, Guo-Wu Escherichia coli Structure-Activity Relationship Organoselenium Compounds Glucuronidase Azoles Enzyme Inhibitors Isoindoles Molecular Structure Dose-Response Relationship, Drug Allosteric Regulation Molecular Docking Simulation Stilbenes Glycoproteins Gut microbial β-glucuronidase (GUS) plays a key role in metabolizing compounds and influencing disease and drug metabolism, highlighting the need for potent inhibitors to improve drug efficacy and intestinal health. To identify Escherichia coli β-glucuronidase (EcGUS) inhibitors, we designed and synthesized fifty 1,2-benzoselenazol-3-one (BSEA) derivatives using a bioisosterism strategy. Among these, twenty-five BSEA derivatives demonstrated greater inhibitory efficacy than the most potent known EcGUS inhibitor, amoxapine (AMX), with compound 49 showing the strongest activity, achieving an IC of 12.9 nM. Structure-inhibitory activity relationship analysis suggested that modifications such as adding benzene rings or nitrogenous heterocycles to the BSEA scaffold enhanced inhibitory activity, influenced by the type and position of substituents. The LC-MS analysis confirmed that compounds 31 and 49 covalently modify Cys197 in EcGUS, and additional covalent linkage of compound 49 was observed on Cys28 and Cys443. In addition, the jump dilution assays proved that compounds 31 was irreversible covalent inhibitors, and its kinetic parameter k/K were determined to be 21292.9 Ms. The compounds 49 was reversible covalent inhibitors and its apparent steady-state inhibition constant K∗ were determined to be 23.33 nM. Molecular docking predicted specific interactions, such as hydrogen bonds involving Se and the pyrazole NH of compound 49 with Cys28 and Cys449, which may contribute to its inhibitory action. This study reports the first discovery of covalent inhibitors for EcGUS, with optimized BSEA derivatives acting as novel allosteric covalent inhibitors, revealing structure-activity relationships and molecular determinants that establish their potential in drug development. |
| title | Optimized ebselen derivatives as novel potent Escherichia coli β-glucuronidase covalent allosteric inhibitors. |
| topic | Escherichia coli Structure-Activity Relationship Organoselenium Compounds Glucuronidase Azoles Enzyme Inhibitors Isoindoles Molecular Structure Dose-Response Relationship, Drug Allosteric Regulation Molecular Docking Simulation Stilbenes Glycoproteins |
| url | https://pubmed.ncbi.nlm.nih.gov/40168911/ |