Stable H-bond networks are crucial for selective CLK1 inhibition: a computational perspective
Studying the selectivity mechanism of inhibitors towards highly similar isoforms is an important task in the development of new drugs, which are designed to avoid the undesired side effects in vivo. CDC-like kinase isoforms (CLKs) are serine/threonine protein kinases that are involved in the phospho...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-06-01
|
| Series: | Frontiers in Chemistry |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2025.1582515/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849689642351198208 |
|---|---|
| author | Yuzhou Huang Yuzhou Huang Baichun Hu Haihan Liu Jian Wang Na Duan |
| author_facet | Yuzhou Huang Yuzhou Huang Baichun Hu Haihan Liu Jian Wang Na Duan |
| author_sort | Yuzhou Huang |
| collection | DOAJ |
| description | Studying the selectivity mechanism of inhibitors towards highly similar isoforms is an important task in the development of new drugs, which are designed to avoid the undesired side effects in vivo. CDC-like kinase isoforms (CLKs) are serine/threonine protein kinases that are involved in the phosphorylation of mRNA spliceosomes leading to the regulation of gene expression. The CLK isoforms are expressed in most human tissues and cells, but the expression levels of each isoform vary in different cells. Typically, CLK3 is expressed in male testes and sperm, by contrast, as a potential cancer treatment target, the expression level of CLK1 in testicular tissue is significantly lower than other isoforms. These differences in the tissue distribution of CLK1 and CLK3 suggest that the development of selective CLK1 inhibitors to avoid potential side effects. Here, our study is designed to reveal the selectivity mechanism of CLK1 inhibition from a computational perspective. In this study, the binding modes of known selective inhibitors towards CLK1/3 are discussed by computational methods such as protein comparison, molecular docking, binding free energy calculation, molecular dynamics simulations, alanine mutagenesis simulations, and quantum mechanical calculation. The simulations reveal selective key roles involved in CLK1/3 binding, including protein-ligand interactions, mutations, and conformational differences in key amino acid residues. This study will contribute to analyze the selectivity mechanism of CLKs inhibitors and bring insight into the development of novel selective inhibitor drugs. |
| format | Article |
| id | doaj-art-0299eea8ea984264baa9dcf4af82ca4e |
| institution | DOAJ |
| issn | 2296-2646 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj-art-0299eea8ea984264baa9dcf4af82ca4e2025-08-20T03:21:32ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462025-06-011310.3389/fchem.2025.15825151582515Stable H-bond networks are crucial for selective CLK1 inhibition: a computational perspectiveYuzhou Huang0Yuzhou Huang1Baichun Hu2Haihan Liu3Jian Wang4Na Duan5Department of Cardiology, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, ChinaKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, ChinaDepartment of Cardiology, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, ChinaStudying the selectivity mechanism of inhibitors towards highly similar isoforms is an important task in the development of new drugs, which are designed to avoid the undesired side effects in vivo. CDC-like kinase isoforms (CLKs) are serine/threonine protein kinases that are involved in the phosphorylation of mRNA spliceosomes leading to the regulation of gene expression. The CLK isoforms are expressed in most human tissues and cells, but the expression levels of each isoform vary in different cells. Typically, CLK3 is expressed in male testes and sperm, by contrast, as a potential cancer treatment target, the expression level of CLK1 in testicular tissue is significantly lower than other isoforms. These differences in the tissue distribution of CLK1 and CLK3 suggest that the development of selective CLK1 inhibitors to avoid potential side effects. Here, our study is designed to reveal the selectivity mechanism of CLK1 inhibition from a computational perspective. In this study, the binding modes of known selective inhibitors towards CLK1/3 are discussed by computational methods such as protein comparison, molecular docking, binding free energy calculation, molecular dynamics simulations, alanine mutagenesis simulations, and quantum mechanical calculation. The simulations reveal selective key roles involved in CLK1/3 binding, including protein-ligand interactions, mutations, and conformational differences in key amino acid residues. This study will contribute to analyze the selectivity mechanism of CLKs inhibitors and bring insight into the development of novel selective inhibitor drugs.https://www.frontiersin.org/articles/10.3389/fchem.2025.1582515/fullCLK1CLK3selective inhibitormolecular dockingmolecular dynamics simulation |
| spellingShingle | Yuzhou Huang Yuzhou Huang Baichun Hu Haihan Liu Jian Wang Na Duan Stable H-bond networks are crucial for selective CLK1 inhibition: a computational perspective Frontiers in Chemistry CLK1 CLK3 selective inhibitor molecular docking molecular dynamics simulation |
| title | Stable H-bond networks are crucial for selective CLK1 inhibition: a computational perspective |
| title_full | Stable H-bond networks are crucial for selective CLK1 inhibition: a computational perspective |
| title_fullStr | Stable H-bond networks are crucial for selective CLK1 inhibition: a computational perspective |
| title_full_unstemmed | Stable H-bond networks are crucial for selective CLK1 inhibition: a computational perspective |
| title_short | Stable H-bond networks are crucial for selective CLK1 inhibition: a computational perspective |
| title_sort | stable h bond networks are crucial for selective clk1 inhibition a computational perspective |
| topic | CLK1 CLK3 selective inhibitor molecular docking molecular dynamics simulation |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2025.1582515/full |
| work_keys_str_mv | AT yuzhouhuang stablehbondnetworksarecrucialforselectiveclk1inhibitionacomputationalperspective AT yuzhouhuang stablehbondnetworksarecrucialforselectiveclk1inhibitionacomputationalperspective AT baichunhu stablehbondnetworksarecrucialforselectiveclk1inhibitionacomputationalperspective AT haihanliu stablehbondnetworksarecrucialforselectiveclk1inhibitionacomputationalperspective AT jianwang stablehbondnetworksarecrucialforselectiveclk1inhibitionacomputationalperspective AT naduan stablehbondnetworksarecrucialforselectiveclk1inhibitionacomputationalperspective |