A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors
IntroductionTo design effective small molecule inhibitors targeting the immune checkpoint PD-1/PD-L1 and to explore their inhibitory activity.MethodsIn this paper, a total of 69 PD-1/PD-L1 inhibitors with the same backbone were searched through opendatabases, and their docking mechanism with PD-L1 p...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2024.1533541/full |
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| author | Meijuan Zhai Shiliang Ji Haoran Hu Yongjie Wu Yi Shi Ruifang Zhu Yiguo Jiang Yang Yang |
| author_facet | Meijuan Zhai Shiliang Ji Haoran Hu Yongjie Wu Yi Shi Ruifang Zhu Yiguo Jiang Yang Yang |
| author_sort | Meijuan Zhai |
| collection | DOAJ |
| description | IntroductionTo design effective small molecule inhibitors targeting the immune checkpoint PD-1/PD-L1 and to explore their inhibitory activity.MethodsIn this paper, a total of 69 PD-1/PD-L1 inhibitors with the same backbone were searched through opendatabases, and their docking mechanism with PD-L1 protein was investigatedby molecular docking method, and the active conformation of the inhibitors was explored. The biological activity of the four newly designed inhibitors was also evaluated using ELISA.ResultsThe most active molecule 58 in the dataset formed six hydrogen bonds with Phe67, Val55, Ile116 and Tyr123, while the second most active molecule 34 formed five hydrogen bonds with Phe67 and Ala121, both of which formed π-π stacking interactions with Tyr56. The analysis of the inhibitor docking results determined that the residues Tyr123, Gln66, Thr20, Met115, Asp122 and Ile116 had the greatest influence on the active conformation of the inhibitor. ELISA assays suggested that the four novel inhibitors designed had high inhibition rates, with the inhibition rate of compound N2 being as high as 68.53%.DiscussionIn this paper, we have designed and synthesized various PD-1/PDL1 inhibitors, which provide a basis for drug discovery targeting the PD-1/PDL1 signaling pathway. |
| format | Article |
| id | doaj-art-fc90be51969642df9b5b0c56f43a8235 |
| institution | Kabale University |
| issn | 2296-2646 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemistry |
| spelling | doaj-art-fc90be51969642df9b5b0c56f43a82352025-01-14T06:10:32ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462025-01-011210.3389/fchem.2024.15335411533541A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitorsMeijuan Zhai0Shiliang Ji1Haoran Hu2Yongjie Wu3Yi Shi4Ruifang Zhu5Yiguo Jiang6Yang Yang7Department of pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou, ChinaSuzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, ChinaState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, ChinaState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, ChinaSuzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, ChinaSuzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, ChinaSuzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, ChinaSuzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, ChinaIntroductionTo design effective small molecule inhibitors targeting the immune checkpoint PD-1/PD-L1 and to explore their inhibitory activity.MethodsIn this paper, a total of 69 PD-1/PD-L1 inhibitors with the same backbone were searched through opendatabases, and their docking mechanism with PD-L1 protein was investigatedby molecular docking method, and the active conformation of the inhibitors was explored. The biological activity of the four newly designed inhibitors was also evaluated using ELISA.ResultsThe most active molecule 58 in the dataset formed six hydrogen bonds with Phe67, Val55, Ile116 and Tyr123, while the second most active molecule 34 formed five hydrogen bonds with Phe67 and Ala121, both of which formed π-π stacking interactions with Tyr56. The analysis of the inhibitor docking results determined that the residues Tyr123, Gln66, Thr20, Met115, Asp122 and Ile116 had the greatest influence on the active conformation of the inhibitor. ELISA assays suggested that the four novel inhibitors designed had high inhibition rates, with the inhibition rate of compound N2 being as high as 68.53%.DiscussionIn this paper, we have designed and synthesized various PD-1/PDL1 inhibitors, which provide a basis for drug discovery targeting the PD-1/PDL1 signaling pathway.https://www.frontiersin.org/articles/10.3389/fchem.2024.1533541/fullnon-small cell lung cancerPD-1 inhibitorPD-L1 inhibitormolecular dockingcomputer-aided drug design |
| spellingShingle | Meijuan Zhai Shiliang Ji Haoran Hu Yongjie Wu Yi Shi Ruifang Zhu Yiguo Jiang Yang Yang A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors Frontiers in Chemistry non-small cell lung cancer PD-1 inhibitor PD-L1 inhibitor molecular docking computer-aided drug design |
| title | A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors |
| title_full | A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors |
| title_fullStr | A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors |
| title_full_unstemmed | A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors |
| title_short | A computational chemistry-based approach to optimizing PD-1/PD-L1 inhibitors |
| title_sort | computational chemistry based approach to optimizing pd 1 pd l1 inhibitors |
| topic | non-small cell lung cancer PD-1 inhibitor PD-L1 inhibitor molecular docking computer-aided drug design |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2024.1533541/full |
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