Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug design
Thioredoxin reductase 1 (TrxR1) is an oxidoreductase playing the important role in the tumor cells. It is a new type of drug therapy target. Most of the existing TrxR1 inhibitors act directly covalently on the active sites. Herein, molecular docking-based virtual screening approach was used to scree...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-04-01
|
| Series: | Arabian Journal of Chemistry |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S187853522300103X |
| _version_ | 1811159990541484032 |
|---|---|
| author | Haoyi Yang Hengyu Wang Jia Feng Jianmin Liao Yuanyuan Lu |
| author_facet | Haoyi Yang Hengyu Wang Jia Feng Jianmin Liao Yuanyuan Lu |
| author_sort | Haoyi Yang |
| collection | DOAJ |
| description | Thioredoxin reductase 1 (TrxR1) is an oxidoreductase playing the important role in the tumor cells. It is a new type of drug therapy target. Most of the existing TrxR1 inhibitors act directly covalently on the active sites. Herein, molecular docking-based virtual screening approach was used to screen inhibitors with new binding site of TrxR1 from the SPECS database. After experimental test, compound 22 was identified as the reversibility inhibitor of TrxR1 U498C mutant (It has similar structure and function to replace the wild-type TrxR1 which is difficult to express) with IC50 value of 15.31 ± 0.57 μM. The molecular docking results showed that the interaction between compound 22 and TrxR1 was centered on inactive site Trp114. Furthermore, phenazine compounds 24–30 with similar structures as 22 were also screened out from our phenazine database. Compounds 24–27 had longer chain structures and better inhibitory activity than compound 22, while compounds 28–30 were the opposite. Compounds 24–27 can be more stably bound in the protein cavity on Trp114 than compounds 28–30. Then we verified amino acids centered on Trp114 can regulate TrxR1 activity by amino acids mutation. Taken together, A new inhibition site are found that can regulate TrxR1 U498C mutant activity by acting on amino acids sequence at inactive sites centered on Trp114 and can provide ideas for the discovery and research of new TrxR1 inhibitors. |
| first_indexed | 2024-04-10T05:50:06Z |
| format | Article |
| id | doaj.art-d292ce29be85419588f2bdec87371141 |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-04-10T05:50:06Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-d292ce29be85419588f2bdec873711412023-03-05T04:24:07ZengElsevierArabian Journal of Chemistry1878-53522023-04-01164104642Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug designHaoyi Yang0Hengyu Wang1Jia Feng2Jianmin Liao3Yuanyuan Lu4China Pharmaceutical University, School of Life Sci & Technol, Nanjing 210009, ChinaChina Pharmaceutical University, School of Life Sci & Technol, Nanjing 210009, ChinaChina Pharmaceutical University, School of Life Sci & Technol, Nanjing 210009, ChinaCorresponding authors at: Department of Marine Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.; China Pharmaceutical University, School of Life Sci & Technol, Nanjing 210009, ChinaCorresponding authors at: Department of Marine Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.; China Pharmaceutical University, School of Life Sci & Technol, Nanjing 210009, ChinaThioredoxin reductase 1 (TrxR1) is an oxidoreductase playing the important role in the tumor cells. It is a new type of drug therapy target. Most of the existing TrxR1 inhibitors act directly covalently on the active sites. Herein, molecular docking-based virtual screening approach was used to screen inhibitors with new binding site of TrxR1 from the SPECS database. After experimental test, compound 22 was identified as the reversibility inhibitor of TrxR1 U498C mutant (It has similar structure and function to replace the wild-type TrxR1 which is difficult to express) with IC50 value of 15.31 ± 0.57 μM. The molecular docking results showed that the interaction between compound 22 and TrxR1 was centered on inactive site Trp114. Furthermore, phenazine compounds 24–30 with similar structures as 22 were also screened out from our phenazine database. Compounds 24–27 had longer chain structures and better inhibitory activity than compound 22, while compounds 28–30 were the opposite. Compounds 24–27 can be more stably bound in the protein cavity on Trp114 than compounds 28–30. Then we verified amino acids centered on Trp114 can regulate TrxR1 activity by amino acids mutation. Taken together, A new inhibition site are found that can regulate TrxR1 U498C mutant activity by acting on amino acids sequence at inactive sites centered on Trp114 and can provide ideas for the discovery and research of new TrxR1 inhibitors.http://www.sciencedirect.com/science/article/pii/S187853522300103XThioredoxin reductase 1Computer-aided drug designVirtual screeningMolecular dockingTrp114 |
| spellingShingle | Haoyi Yang Hengyu Wang Jia Feng Jianmin Liao Yuanyuan Lu Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug design Arabian Journal of Chemistry Thioredoxin reductase 1 Computer-aided drug design Virtual screening Molecular docking Trp114 |
| title | Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug design |
| title_full | Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug design |
| title_fullStr | Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug design |
| title_full_unstemmed | Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug design |
| title_short | Discovery of novel inhibition site centered on 114-bit tryptophan of Thioredoxin reductase 1 through computer-aided drug design |
| title_sort | discovery of novel inhibition site centered on 114 bit tryptophan of thioredoxin reductase 1 through computer aided drug design |
| topic | Thioredoxin reductase 1 Computer-aided drug design Virtual screening Molecular docking Trp114 |
| url | http://www.sciencedirect.com/science/article/pii/S187853522300103X |
| work_keys_str_mv | AT haoyiyang discoveryofnovelinhibitionsitecenteredon114bittryptophanofthioredoxinreductase1throughcomputeraideddrugdesign AT hengyuwang discoveryofnovelinhibitionsitecenteredon114bittryptophanofthioredoxinreductase1throughcomputeraideddrugdesign AT jiafeng discoveryofnovelinhibitionsitecenteredon114bittryptophanofthioredoxinreductase1throughcomputeraideddrugdesign AT jianminliao discoveryofnovelinhibitionsitecenteredon114bittryptophanofthioredoxinreductase1throughcomputeraideddrugdesign AT yuanyuanlu discoveryofnovelinhibitionsitecenteredon114bittryptophanofthioredoxinreductase1throughcomputeraideddrugdesign |