Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study
In cancer immunotherapy, an emerging approach is to block the interactions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) using small-molecule inhibitors. The food-derived polyphenols curcumin (CC), resveratrol (RSV) and epigallocatechin gallate (EGCG) have anticancer i...
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| Format: | Article |
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/20/10924 |
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| author | Yan Guo Jianhuai Liang Boping Liu Yulong Jin |
| author_facet | Yan Guo Jianhuai Liang Boping Liu Yulong Jin |
| author_sort | Yan Guo |
| collection | DOAJ |
| description | In cancer immunotherapy, an emerging approach is to block the interactions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) using small-molecule inhibitors. The food-derived polyphenols curcumin (CC), resveratrol (RSV) and epigallocatechin gallate (EGCG) have anticancer immunologic functions, which, recently, have been proposed to act via the downregulation of PD-L1 expression. However, it remains unclear whether they can directly target PD-L1 dimerization and, thus, interrupt the PD-1/PD-L1 pathway. To elucidate the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and nanosecond molecular dynamics simulations were performed. Binding free energy calculations show that the affinities of CC, RSV and EGCG to the PD-L1 dimer follow a trend of CC > RSV > EGCG. Hence, CC is the most effective inhibitor of the PD-1/PD-L1 pathway. Analysis on contact numbers, nonbonded interactions and residue energy decomposition indicate that such compounds mainly interact with the C-, F- and G-sheet fragments of the PD-L1 dimer, which are involved in interactions with PD-1. More importantly, nonpolar interactions between these compounds and the key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 play a dominant role in binding. Free energy landscape and secondary structure analyses further demonstrate that such compounds can stably interact with the binding domain of the PD-L1 dimer. The results provide evidence that CC, RSV and EGCG can inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. This provides a novel approach to discovering food-derived small-molecule inhibitors of the PD-1/PD-L1 pathway with potential applications in cancer immunotherapy. |
| first_indexed | 2024-03-10T06:30:45Z |
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| language | English |
| last_indexed | 2024-03-10T06:30:45Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-62bbd0e3599546b7a7cfd0ed08d7fb5c2023-11-22T18:30:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122201092410.3390/ijms222010924Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation StudyYan Guo0Jianhuai Liang1Boping Liu2Yulong Jin3Key Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510630, ChinaKey Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510630, ChinaKey Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510630, ChinaKey Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510630, ChinaIn cancer immunotherapy, an emerging approach is to block the interactions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) using small-molecule inhibitors. The food-derived polyphenols curcumin (CC), resveratrol (RSV) and epigallocatechin gallate (EGCG) have anticancer immunologic functions, which, recently, have been proposed to act via the downregulation of PD-L1 expression. However, it remains unclear whether they can directly target PD-L1 dimerization and, thus, interrupt the PD-1/PD-L1 pathway. To elucidate the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and nanosecond molecular dynamics simulations were performed. Binding free energy calculations show that the affinities of CC, RSV and EGCG to the PD-L1 dimer follow a trend of CC > RSV > EGCG. Hence, CC is the most effective inhibitor of the PD-1/PD-L1 pathway. Analysis on contact numbers, nonbonded interactions and residue energy decomposition indicate that such compounds mainly interact with the C-, F- and G-sheet fragments of the PD-L1 dimer, which are involved in interactions with PD-1. More importantly, nonpolar interactions between these compounds and the key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 play a dominant role in binding. Free energy landscape and secondary structure analyses further demonstrate that such compounds can stably interact with the binding domain of the PD-L1 dimer. The results provide evidence that CC, RSV and EGCG can inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. This provides a novel approach to discovering food-derived small-molecule inhibitors of the PD-1/PD-L1 pathway with potential applications in cancer immunotherapy.https://www.mdpi.com/1422-0067/22/20/10924PD-1/PD-L1 pathwayfood-derived polyphenolssmall-molecule inhibitorsmolecular dockingmolecular dynamics simulation |
| spellingShingle | Yan Guo Jianhuai Liang Boping Liu Yulong Jin Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study International Journal of Molecular Sciences PD-1/PD-L1 pathway food-derived polyphenols small-molecule inhibitors molecular docking molecular dynamics simulation |
| title | Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study |
| title_full | Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study |
| title_fullStr | Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study |
| title_full_unstemmed | Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study |
| title_short | Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study |
| title_sort | molecular mechanism of food derived polyphenols on pd l1 dimerization a molecular dynamics simulation study |
| topic | PD-1/PD-L1 pathway food-derived polyphenols small-molecule inhibitors molecular docking molecular dynamics simulation |
| url | https://www.mdpi.com/1422-0067/22/20/10924 |
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