Hydroxyethylamine based analog targets microtubule assembly: an in silico study for anti-cancerous drug development
Abstract Microtubules are dynamic cytoskeletal structures essential for cell architecture, cellular transport, cell motility, and cell division. Due to their dynamic nature, known as dynamic instability, microtubules can spontaneously switch between phases of growth and shortening. Disruptions in mi...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-82823-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850086615095967744 |
|---|---|
| author | Pawan Kumar Rajni Khan Basant Narain Singh Anisha Kumari Ankit Rai Anil Kumar Singh Amresh Prakash Shashikant Ray |
| author_facet | Pawan Kumar Rajni Khan Basant Narain Singh Anisha Kumari Ankit Rai Anil Kumar Singh Amresh Prakash Shashikant Ray |
| author_sort | Pawan Kumar |
| collection | DOAJ |
| description | Abstract Microtubules are dynamic cytoskeletal structures essential for cell architecture, cellular transport, cell motility, and cell division. Due to their dynamic nature, known as dynamic instability, microtubules can spontaneously switch between phases of growth and shortening. Disruptions in microtubule functions have been implicated in several diseases, including cancer, neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, and birth defects. The role of microtubules during various phases of the cell cycle, particularly in cell division, makes them attractive targets for drug development against cancer. Several successful drugs currently on the market are designed to target microtubules. However, the presence of cellular toxicity and the development of multidrug resistance necessitate the search for new microtubule-targeting drugs.Here, a library of 106 biologically active compounds were screened to identify potent microtubule assembly inhibitors. Out of all the screened compounds, the hydroxyethylamine (HEA) analogues are found to be the best hit.We identified three inhibitors, BKS3031A, BKS3045A and BKS3046A, that bind at the same site as the well-known microtubule targeting agent colchicine. These inhibitors were simulated for 100 ns with tubulin complexes, and the results indicated that they remain stable within the binding pocket of α-β tubulin complexes. In addition, we estimated the binding free energy of BKS3031A, BKS3045A and BKS3046A by using molecular mechanics generalized Born surface area (MM-GBSA) calculations, and it was found to be -32.67 ± 6.01, -21.77 ± 5.12 and − 22.92 ± 5.09 kcal/mol, respectively. Our findings suggest that these novel inhibitors have potential to bind and perturb the microtubule network, positioning them as promising microtubule-targeting agents. |
| format | Article |
| id | doaj-art-4fd83c595d8a422780af20b7d77f8dfa |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-4fd83c595d8a422780af20b7d77f8dfa2025-08-20T02:43:25ZengNature PortfolioScientific Reports2045-23222024-12-0114111210.1038/s41598-024-82823-8Hydroxyethylamine based analog targets microtubule assembly: an in silico study for anti-cancerous drug developmentPawan Kumar0Rajni Khan1Basant Narain Singh2Anisha Kumari3Ankit Rai4Anil Kumar Singh5Amresh Prakash6Shashikant Ray7School of Computational and Integrative Sciences, Jawaharlal Nehru UniversityDepartment of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and ResearchDepartment of Botany, Pandit Deendayal Upadhyaya Shekhawati UniversityDepartment of Biotechnology, Mahatma Gandhi Central UniversityDepartment of Medical Biotechnology, Gujrat Biotechnology UniversityDepartment of Chemistry, Mahatma Gandhi Central UniversityAmity Institute of Integrative Sciences and Health, Amity University HaryanaDepartment of Biotechnology, Mahatma Gandhi Central UniversityAbstract Microtubules are dynamic cytoskeletal structures essential for cell architecture, cellular transport, cell motility, and cell division. Due to their dynamic nature, known as dynamic instability, microtubules can spontaneously switch between phases of growth and shortening. Disruptions in microtubule functions have been implicated in several diseases, including cancer, neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, and birth defects. The role of microtubules during various phases of the cell cycle, particularly in cell division, makes them attractive targets for drug development against cancer. Several successful drugs currently on the market are designed to target microtubules. However, the presence of cellular toxicity and the development of multidrug resistance necessitate the search for new microtubule-targeting drugs.Here, a library of 106 biologically active compounds were screened to identify potent microtubule assembly inhibitors. Out of all the screened compounds, the hydroxyethylamine (HEA) analogues are found to be the best hit.We identified three inhibitors, BKS3031A, BKS3045A and BKS3046A, that bind at the same site as the well-known microtubule targeting agent colchicine. These inhibitors were simulated for 100 ns with tubulin complexes, and the results indicated that they remain stable within the binding pocket of α-β tubulin complexes. In addition, we estimated the binding free energy of BKS3031A, BKS3045A and BKS3046A by using molecular mechanics generalized Born surface area (MM-GBSA) calculations, and it was found to be -32.67 ± 6.01, -21.77 ± 5.12 and − 22.92 ± 5.09 kcal/mol, respectively. Our findings suggest that these novel inhibitors have potential to bind and perturb the microtubule network, positioning them as promising microtubule-targeting agents.https://doi.org/10.1038/s41598-024-82823-8Αβ-tubulinMD simulationMM-GBSA |
| spellingShingle | Pawan Kumar Rajni Khan Basant Narain Singh Anisha Kumari Ankit Rai Anil Kumar Singh Amresh Prakash Shashikant Ray Hydroxyethylamine based analog targets microtubule assembly: an in silico study for anti-cancerous drug development Scientific Reports Αβ-tubulin MD simulation MM-GBSA |
| title | Hydroxyethylamine based analog targets microtubule assembly: an in silico study for anti-cancerous drug development |
| title_full | Hydroxyethylamine based analog targets microtubule assembly: an in silico study for anti-cancerous drug development |
| title_fullStr | Hydroxyethylamine based analog targets microtubule assembly: an in silico study for anti-cancerous drug development |
| title_full_unstemmed | Hydroxyethylamine based analog targets microtubule assembly: an in silico study for anti-cancerous drug development |
| title_short | Hydroxyethylamine based analog targets microtubule assembly: an in silico study for anti-cancerous drug development |
| title_sort | hydroxyethylamine based analog targets microtubule assembly an in silico study for anti cancerous drug development |
| topic | Αβ-tubulin MD simulation MM-GBSA |
| url | https://doi.org/10.1038/s41598-024-82823-8 |
| work_keys_str_mv | AT pawankumar hydroxyethylaminebasedanalogtargetsmicrotubuleassemblyaninsilicostudyforanticancerousdrugdevelopment AT rajnikhan hydroxyethylaminebasedanalogtargetsmicrotubuleassemblyaninsilicostudyforanticancerousdrugdevelopment AT basantnarainsingh hydroxyethylaminebasedanalogtargetsmicrotubuleassemblyaninsilicostudyforanticancerousdrugdevelopment AT anishakumari hydroxyethylaminebasedanalogtargetsmicrotubuleassemblyaninsilicostudyforanticancerousdrugdevelopment AT ankitrai hydroxyethylaminebasedanalogtargetsmicrotubuleassemblyaninsilicostudyforanticancerousdrugdevelopment AT anilkumarsingh hydroxyethylaminebasedanalogtargetsmicrotubuleassemblyaninsilicostudyforanticancerousdrugdevelopment AT amreshprakash hydroxyethylaminebasedanalogtargetsmicrotubuleassemblyaninsilicostudyforanticancerousdrugdevelopment AT shashikantray hydroxyethylaminebasedanalogtargetsmicrotubuleassemblyaninsilicostudyforanticancerousdrugdevelopment |