Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation
AbstractAbnormal accumulation of branched-chain amino acids (BCAAs) can lead to metabolic diseases and cancers. Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a key negative regulator of BCAA catabolism, and targeting BCKDK provides a promising therapeutic approach for diseases caused by...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2290458 |
| _version_ | 1797401531963670528 |
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| author | Chunqiong Li Quanjun Yang Li Zhang |
| author_facet | Chunqiong Li Quanjun Yang Li Zhang |
| author_sort | Chunqiong Li |
| collection | DOAJ |
| description | AbstractAbnormal accumulation of branched-chain amino acids (BCAAs) can lead to metabolic diseases and cancers. Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a key negative regulator of BCAA catabolism, and targeting BCKDK provides a promising therapeutic approach for diseases caused by BCAA accumulation. Here, we screened PPHN and POAB as novel putative allosteric inhibitors by integrating allosteric binding site prediction, large-scale ligand database virtual screening, and bioactivity evaluation assays. Both of them showed a high binding affinity to BCKDK, with Kd values of 3.9 μM and 1.86 μM, respectively. In vivo experiments, the inhibitors demonstrated superior kinase inhibitory activity and notable antiproliferative and proapoptotic effects on diverse cancer cells. Finally, bulk RNA-seq analysis revealed that PPHN and POAB suppressed cell growth through a range of signalling pathways. Taken together, our findings highlight two novel BCKDK inhibitors as potent therapeutic candidates for metabolic diseases and cancers associated with BCAA dysfunctional metabolism. |
| first_indexed | 2024-03-09T02:11:27Z |
| format | Article |
| id | doaj.art-25b42912963b48479ae5338a0038c07a |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-03-09T02:11:27Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-25b42912963b48479ae5338a0038c07a2023-12-07T09:06:32ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2023.2290458Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluationChunqiong Li0Quanjun Yang1Li Zhang2Genomics Center, Chinese Institute for Brain Research, Beijing, ChinaDepartment of Pharmacy, Shanghai Sixth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaGenomics Center, Chinese Institute for Brain Research, Beijing, ChinaAbstractAbnormal accumulation of branched-chain amino acids (BCAAs) can lead to metabolic diseases and cancers. Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a key negative regulator of BCAA catabolism, and targeting BCKDK provides a promising therapeutic approach for diseases caused by BCAA accumulation. Here, we screened PPHN and POAB as novel putative allosteric inhibitors by integrating allosteric binding site prediction, large-scale ligand database virtual screening, and bioactivity evaluation assays. Both of them showed a high binding affinity to BCKDK, with Kd values of 3.9 μM and 1.86 μM, respectively. In vivo experiments, the inhibitors demonstrated superior kinase inhibitory activity and notable antiproliferative and proapoptotic effects on diverse cancer cells. Finally, bulk RNA-seq analysis revealed that PPHN and POAB suppressed cell growth through a range of signalling pathways. Taken together, our findings highlight two novel BCKDK inhibitors as potent therapeutic candidates for metabolic diseases and cancers associated with BCAA dysfunctional metabolism.https://www.tandfonline.com/doi/10.1080/14756366.2023.2290458BCKDKallosteric inhibitorsvirtual screeningBCAA metabolismmetabolic diseases and cancer treatment |
| spellingShingle | Chunqiong Li Quanjun Yang Li Zhang Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation Journal of Enzyme Inhibition and Medicinal Chemistry BCKDK allosteric inhibitors virtual screening BCAA metabolism metabolic diseases and cancer treatment |
| title | Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation |
| title_full | Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation |
| title_fullStr | Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation |
| title_full_unstemmed | Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation |
| title_short | Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation |
| title_sort | identification of putative allosteric inhibitors of bckdk via virtual screening and biological evaluation |
| topic | BCKDK allosteric inhibitors virtual screening BCAA metabolism metabolic diseases and cancer treatment |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2290458 |
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