The study of halogen effect on the reactivity of the serine-targeting covalent warheads
Halogens favorably contributes to the drug potency and metabolic stability via electrostatic interactions. Herein, the halogen effects on the reactivity of the halogenated 2,2,2-trifluoroacetophenones as serine-targeting covalent warheads were investigated. Our results showed that introducing haloge...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-12-01
|
| Series: | Frontiers in Chemistry |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2024.1504453/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846143048921120768 |
|---|---|
| author | Conghao Gai Ya Zhang Shihao Zhang Xueyan Hu Yun-Qing Song Xiaoyu Zhuang Xiaoyun Chai Yan Zou Guang-Bo Ge Qingjie Zhao |
| author_facet | Conghao Gai Ya Zhang Shihao Zhang Xueyan Hu Yun-Qing Song Xiaoyu Zhuang Xiaoyun Chai Yan Zou Guang-Bo Ge Qingjie Zhao |
| author_sort | Conghao Gai |
| collection | DOAJ |
| description | Halogens favorably contributes to the drug potency and metabolic stability via electrostatic interactions. Herein, the halogen effects on the reactivity of the halogenated 2,2,2-trifluoroacetophenones as serine-targeting covalent warheads were investigated. Our results showed that introducing halogen atoms, especially Cl or Br, into the phenyl scaffold would influence the electron density around the ring, which led to different time-dependent inhibition response to the target serine hydrolase (hCES1A). Co-crystallography analysis not only verified that halogenated molecules preferred to form covalent adducts, but also provided the conformational information for the design of covalent inhibitors targeting to hCES1A protein for the treatment of drug-induced acute enteritis. |
| format | Article |
| id | doaj-art-0c8c4cba18d54a248c93495bb8797e96 |
| institution | Kabale University |
| issn | 2296-2646 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj-art-0c8c4cba18d54a248c93495bb8797e962024-12-03T04:22:56ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462024-12-011210.3389/fchem.2024.15044531504453The study of halogen effect on the reactivity of the serine-targeting covalent warheadsConghao Gai0Ya Zhang1Shihao Zhang2Xueyan Hu3Yun-Qing Song4Xiaoyu Zhuang5Xiaoyun Chai6Yan Zou7Guang-Bo Ge8Qingjie Zhao9Organic Chemistry Group, College of Pharmacy, Naval Medical University, Shanghai, ChinaShanghai Frontiers Science Centre of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaOrganic Chemistry Group, College of Pharmacy, Naval Medical University, Shanghai, ChinaShanghai Frontiers Science Centre of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaShanghai Frontiers Science Centre of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaShanghai Frontiers Science Centre of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaOrganic Chemistry Group, College of Pharmacy, Naval Medical University, Shanghai, ChinaOrganic Chemistry Group, College of Pharmacy, Naval Medical University, Shanghai, ChinaShanghai Frontiers Science Centre of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaOrganic Chemistry Group, College of Pharmacy, Naval Medical University, Shanghai, ChinaHalogens favorably contributes to the drug potency and metabolic stability via electrostatic interactions. Herein, the halogen effects on the reactivity of the halogenated 2,2,2-trifluoroacetophenones as serine-targeting covalent warheads were investigated. Our results showed that introducing halogen atoms, especially Cl or Br, into the phenyl scaffold would influence the electron density around the ring, which led to different time-dependent inhibition response to the target serine hydrolase (hCES1A). Co-crystallography analysis not only verified that halogenated molecules preferred to form covalent adducts, but also provided the conformational information for the design of covalent inhibitors targeting to hCES1A protein for the treatment of drug-induced acute enteritis.https://www.frontiersin.org/articles/10.3389/fchem.2024.1504453/fullhCES1Acovalent warheads2,2,2-trifluoroacetophenonesserine-targeted reactivityhalogen effect |
| spellingShingle | Conghao Gai Ya Zhang Shihao Zhang Xueyan Hu Yun-Qing Song Xiaoyu Zhuang Xiaoyun Chai Yan Zou Guang-Bo Ge Qingjie Zhao The study of halogen effect on the reactivity of the serine-targeting covalent warheads Frontiers in Chemistry hCES1A covalent warheads 2,2,2-trifluoroacetophenones serine-targeted reactivity halogen effect |
| title | The study of halogen effect on the reactivity of the serine-targeting covalent warheads |
| title_full | The study of halogen effect on the reactivity of the serine-targeting covalent warheads |
| title_fullStr | The study of halogen effect on the reactivity of the serine-targeting covalent warheads |
| title_full_unstemmed | The study of halogen effect on the reactivity of the serine-targeting covalent warheads |
| title_short | The study of halogen effect on the reactivity of the serine-targeting covalent warheads |
| title_sort | study of halogen effect on the reactivity of the serine targeting covalent warheads |
| topic | hCES1A covalent warheads 2,2,2-trifluoroacetophenones serine-targeted reactivity halogen effect |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2024.1504453/full |
| work_keys_str_mv | AT conghaogai thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT yazhang thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT shihaozhang thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT xueyanhu thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT yunqingsong thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT xiaoyuzhuang thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT xiaoyunchai thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT yanzou thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT guangboge thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT qingjiezhao thestudyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT conghaogai studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT yazhang studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT shihaozhang studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT xueyanhu studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT yunqingsong studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT xiaoyuzhuang studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT xiaoyunchai studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT yanzou studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT guangboge studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads AT qingjiezhao studyofhalogeneffectonthereactivityoftheserinetargetingcovalentwarheads |