Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease
Zika virus (ZIKV) NS2B-NS3 protease is a validated antiviral target as it is essential for maturation of viral proteins. However, its negatively charged active site hinders the development of orthosteric small-molecule inhibitors. Fragment-based drug discovery (FBDD) is a powerful tool to generate n...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2020
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| Online Access: | https://hdl.handle.net/10356/140769 |
| _version_ | 1826122703158902784 |
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| author | Quek, Jun Ping Liu, Shuang Zhang, Zhenzhen Li, Yan Ng, Elizabeth Yihui Loh, Ying Ru Hung, Alvin W. Luo, Dahai Kang, CongBao |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Quek, Jun Ping Liu, Shuang Zhang, Zhenzhen Li, Yan Ng, Elizabeth Yihui Loh, Ying Ru Hung, Alvin W. Luo, Dahai Kang, CongBao |
| author_sort | Quek, Jun Ping |
| collection | NTU |
| description | Zika virus (ZIKV) NS2B-NS3 protease is a validated antiviral target as it is essential for maturation of viral proteins. However, its negatively charged active site hinders the development of orthosteric small-molecule inhibitors. Fragment-based drug discovery (FBDD) is a powerful tool to generate novel chemical starting points against difficult drug targets. In this study, we scre ened a fragment compound library against the Zika protease using a primary thermal shift assay and identified twenty-two fragments which (bind to and) stabilize the protease. We then determined the X-ray crystal structures of two hits from different classes, all of which bind to the S1 pocket of the protease. We confirmed that these two fragments bind to the protease without inducing significant conformational changes using solution NMR spectroscopy. These fragment scaffolds serve as the starting point for subsequent lead compound development. |
| first_indexed | 2024-10-01T05:52:32Z |
| format | Journal Article |
| id | ntu-10356/140769 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:52:32Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1407692021-01-28T07:15:55Z Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease Quek, Jun Ping Liu, Shuang Zhang, Zhenzhen Li, Yan Ng, Elizabeth Yihui Loh, Ying Ru Hung, Alvin W. Luo, Dahai Kang, CongBao Lee Kong Chian School of Medicine (LKCMedicine) NTU Institute of Structural Biology 4G Research Lab Science::Medicine Zika Virus Fragment-based Drug Discovery Zika virus (ZIKV) NS2B-NS3 protease is a validated antiviral target as it is essential for maturation of viral proteins. However, its negatively charged active site hinders the development of orthosteric small-molecule inhibitors. Fragment-based drug discovery (FBDD) is a powerful tool to generate novel chemical starting points against difficult drug targets. In this study, we scre ened a fragment compound library against the Zika protease using a primary thermal shift assay and identified twenty-two fragments which (bind to and) stabilize the protease. We then determined the X-ray crystal structures of two hits from different classes, all of which bind to the S1 pocket of the protease. We confirmed that these two fragments bind to the protease without inducing significant conformational changes using solution NMR spectroscopy. These fragment scaffolds serve as the starting point for subsequent lead compound development. Accepted version 2020-06-02T02:07:01Z 2020-06-02T02:07:01Z 2020 Journal Article Quek, J. P., Liu, S., Zhang, Z., Li, Y., Ng, E. Y., Loh, Y. R., . . . Kang, C. (2020). Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease. Antiviral Research, 175, 104707-. doi:10.1016/j.antiviral.2020.104707 0166-3542 https://hdl.handle.net/10356/140769 10.1016/j.antiviral.2020.104707 31953156 2-s2.0-85077996695 175 en Antiviral Research © 2020 Elsevier B.V. All rights reserved. This paper was published in Antiviral Research and is made available with permission of Elsevier B.V. application/pdf |
| spellingShingle | Science::Medicine Zika Virus Fragment-based Drug Discovery Quek, Jun Ping Liu, Shuang Zhang, Zhenzhen Li, Yan Ng, Elizabeth Yihui Loh, Ying Ru Hung, Alvin W. Luo, Dahai Kang, CongBao Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease |
| title | Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease |
| title_full | Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease |
| title_fullStr | Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease |
| title_full_unstemmed | Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease |
| title_short | Identification and structural characterization of small molecule fragments targeting Zika virus NS2B-NS3 protease |
| title_sort | identification and structural characterization of small molecule fragments targeting zika virus ns2b ns3 protease |
| topic | Science::Medicine Zika Virus Fragment-based Drug Discovery |
| url | https://hdl.handle.net/10356/140769 |
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