Fragment-based drug discovery and mechanistic studies of human thymidylate synthase
Human thymidylate synthase (hTS) is the sole enzyme responsible for de novo biosynthesis of dTMP and is vital to cell proliferation and survival. Inhibition of hTS has been explored and found to be effective in cancer chemotherapy, while the efficacy is limited by drug resistance. Herein fragment sc...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis-Doctor of Philosophy |
| Language: | English |
| Published: |
Nanyang Technological University
2016
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/65932 |
| _version_ | 1826120229243060224 |
|---|---|
| author | Chen, Dan |
| author2 | - |
| author_facet | - Chen, Dan |
| author_sort | Chen, Dan |
| collection | NTU |
| description | Human thymidylate synthase (hTS) is the sole enzyme responsible for de novo biosynthesis of dTMP and is vital to cell proliferation and survival. Inhibition of hTS has been explored and found to be effective in cancer chemotherapy, while the efficacy is limited by drug resistance. Herein fragment screening is applied to hTS to identify novel start point for drug design. Four types of hits are found, of which two are progressed to structure- and biophysics-driven drug design due to novel binding modes in the active site. The elaborated compounds show significant improvements in affinities and open new avenues for development of hTS inhibitors to overcome drug resistance. Meanwhile, another type of hit reveals a potential allosteric site of hTS possibly involved in regulating overexpression-induced drug resistance to hTS inhibitors. |
| first_indexed | 2024-10-01T05:13:06Z |
| format | Thesis-Doctor of Philosophy |
| id | ntu-10356/65932 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:13:06Z |
| publishDate | 2016 |
| publisher | Nanyang Technological University |
| record_format | dspace |
| spelling | ntu-10356/659322023-02-28T18:39:55Z Fragment-based drug discovery and mechanistic studies of human thymidylate synthase Chen, Dan - School of Biological Sciences Nordlund Paer Lennart - DRNTU::Science::Biological sciences::Molecular biology Human thymidylate synthase (hTS) is the sole enzyme responsible for de novo biosynthesis of dTMP and is vital to cell proliferation and survival. Inhibition of hTS has been explored and found to be effective in cancer chemotherapy, while the efficacy is limited by drug resistance. Herein fragment screening is applied to hTS to identify novel start point for drug design. Four types of hits are found, of which two are progressed to structure- and biophysics-driven drug design due to novel binding modes in the active site. The elaborated compounds show significant improvements in affinities and open new avenues for development of hTS inhibitors to overcome drug resistance. Meanwhile, another type of hit reveals a potential allosteric site of hTS possibly involved in regulating overexpression-induced drug resistance to hTS inhibitors. Doctor of Philosophy 2016-01-29T02:53:41Z 2016-01-29T02:53:41Z 2016 Thesis-Doctor of Philosophy https://hdl.handle.net/10356/65932 10.32657/10356/65932 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). 176 p. application/pdf Nanyang Technological University |
| spellingShingle | DRNTU::Science::Biological sciences::Molecular biology Chen, Dan Fragment-based drug discovery and mechanistic studies of human thymidylate synthase |
| title | Fragment-based drug discovery and mechanistic studies of human thymidylate synthase |
| title_full | Fragment-based drug discovery and mechanistic studies of human thymidylate synthase |
| title_fullStr | Fragment-based drug discovery and mechanistic studies of human thymidylate synthase |
| title_full_unstemmed | Fragment-based drug discovery and mechanistic studies of human thymidylate synthase |
| title_short | Fragment-based drug discovery and mechanistic studies of human thymidylate synthase |
| title_sort | fragment based drug discovery and mechanistic studies of human thymidylate synthase |
| topic | DRNTU::Science::Biological sciences::Molecular biology |
| url | https://hdl.handle.net/10356/65932 |
| work_keys_str_mv | AT chendan fragmentbaseddrugdiscoveryandmechanisticstudiesofhumanthymidylatesynthase |