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Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization

Programmed cell death-1 (PD-1), which is a molecule involved in the inhibitory signal in the immune system and is important due to blocking of the interactions between PD-1 and programmed cell death ligand-1 (PD-L1), has emerged as a promising immunotherapy for treating cancer. In this work, molecul...

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Autores principales: Guo, Yan, Jin, Yulong, Wang, Bingfeng, Liu, Boping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125578/
https://www.ncbi.nlm.nih.gov/pubmed/33946261
http://dx.doi.org/10.3390/ijms22094766
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author Guo, Yan
Jin, Yulong
Wang, Bingfeng
Liu, Boping
author_facet Guo, Yan
Jin, Yulong
Wang, Bingfeng
Liu, Boping
author_sort Guo, Yan
collection PubMed
description Programmed cell death-1 (PD-1), which is a molecule involved in the inhibitory signal in the immune system and is important due to blocking of the interactions between PD-1 and programmed cell death ligand-1 (PD-L1), has emerged as a promising immunotherapy for treating cancer. In this work, molecular dynamics simulations were performed on complex systems consisting of the PD-L1 dimer with (S)-BMS-200, (R)-BMS-200 and (MOD)-BMS-200 (i.e., S, R and MOD systems) to systematically evaluate the inhibitory mechanism of BMS-200-related small-molecule inhibitors in detail. Among them, (MOD)-BMS-200 was modified from the original (S)-BMS-200 by replacing the hydroxyl group with a carbonyl to remove its chirality. Binding free energy analysis indicates that BMS-200-related inhibitors can promote the dimerization of PD-L1. Meanwhile, no significant differences were observed between the S and MOD systems, though the R system exhibited a slightly higher energy. Residue energy decomposition, nonbonded interaction, and contact number analyses show that the inhibitors mainly bind with the C, F and G regions of the PD-L1 dimer, while nonpolar interactions of key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 on both PD-L1 monomers are the dominant binding-related stability factors. Furthermore, compared with (S)-BMS-200, (R)-BMS-200 is more likely to form hydrogen bonds with charged residues. Finally, free energy landscape and protein–protein interaction analyses show that the key residues of the PD-L1 dimer undergo remarkable conformational changes induced by (S)-BMS-200, which boosts its intimate interactions. This systematic investigation provides a comprehensive molecular insight into the ligand recognition process, which will benefit the design of new small-molecule inhibitors targeting PD-L1 for use in anticancer therapy.
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spelling pubmed-81255782021-05-17 Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization Guo, Yan Jin, Yulong Wang, Bingfeng Liu, Boping Int J Mol Sci Article Programmed cell death-1 (PD-1), which is a molecule involved in the inhibitory signal in the immune system and is important due to blocking of the interactions between PD-1 and programmed cell death ligand-1 (PD-L1), has emerged as a promising immunotherapy for treating cancer. In this work, molecular dynamics simulations were performed on complex systems consisting of the PD-L1 dimer with (S)-BMS-200, (R)-BMS-200 and (MOD)-BMS-200 (i.e., S, R and MOD systems) to systematically evaluate the inhibitory mechanism of BMS-200-related small-molecule inhibitors in detail. Among them, (MOD)-BMS-200 was modified from the original (S)-BMS-200 by replacing the hydroxyl group with a carbonyl to remove its chirality. Binding free energy analysis indicates that BMS-200-related inhibitors can promote the dimerization of PD-L1. Meanwhile, no significant differences were observed between the S and MOD systems, though the R system exhibited a slightly higher energy. Residue energy decomposition, nonbonded interaction, and contact number analyses show that the inhibitors mainly bind with the C, F and G regions of the PD-L1 dimer, while nonpolar interactions of key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 on both PD-L1 monomers are the dominant binding-related stability factors. Furthermore, compared with (S)-BMS-200, (R)-BMS-200 is more likely to form hydrogen bonds with charged residues. Finally, free energy landscape and protein–protein interaction analyses show that the key residues of the PD-L1 dimer undergo remarkable conformational changes induced by (S)-BMS-200, which boosts its intimate interactions. This systematic investigation provides a comprehensive molecular insight into the ligand recognition process, which will benefit the design of new small-molecule inhibitors targeting PD-L1 for use in anticancer therapy. MDPI 2021-04-30 /pmc/articles/PMC8125578/ /pubmed/33946261 http://dx.doi.org/10.3390/ijms22094766 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guo, Yan
Jin, Yulong
Wang, Bingfeng
Liu, Boping
Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization
title Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization
title_full Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization
title_fullStr Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization
title_full_unstemmed Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization
title_short Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization
title_sort molecular mechanism of small-molecule inhibitors in blocking the pd-1/pd-l1 pathway through pd-l1 dimerization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125578/
https://www.ncbi.nlm.nih.gov/pubmed/33946261
http://dx.doi.org/10.3390/ijms22094766
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