Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/PD-L1 Pathway through PD-L1 Dimerization
| Autor: | Bing-Feng Wang, Yan Guo, Yulong Jin, Boping Liu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
PD-L1 Stereochemistry QH301-705.5 Dimer Programmed Cell Death 1 Receptor Molecular Dynamics Simulation Catalysis B7-H1 Antigen Article Inorganic Chemistry Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Molecular dynamics 0302 clinical medicine Molecule Humans Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy binding free energy Hydrogen bond Organic Chemistry digestive oral and skin physiology BMS-200-related small-molecule inhibitor Energy landscape General Medicine molecular docking Ligand (biochemistry) Small molecule Computer Science Applications Molecular Docking Simulation Chemistry stomatognathic diseases 030104 developmental biology chemistry 030220 oncology & carcinogenesis Thermodynamics Protein Multimerization Chirality (chemistry) Signal Transduction |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 4766, p 4766 (2021) Volume 22 Issue 9 |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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