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

doi:10.3390/ijms22094766

Cited by 27 publications

(28 citation statements)

References 62 publications

(95 reference statements)

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“…The pocket of the EGCG system was surrounded by residues A Phe19, A Thr20, A Ala121, A Asp122, A Tyr123, A Lys124, B Ile54, B Tyr56, B Gln66, B Val68 and B Met115, among which the sidechain of B Gln66 was near the O37 atom of EGCG and the others neighbored the aromatic rings of EGCG. Briefly, the interaction modes between the PD-L1 dimer and food-derived compounds were in good concordance with those of the PD-L1 dimer and BMS small-molecules, as well as the [1,2,4] triazolo [4,3-a] pyridines inhibitors [40][41][42][43][44][45]. In particular, the residues located at the binding pockets-Ile54, Tyr56, Met115, Ala121 and Tyr12-were highly conservative.…”

Section: Nonbonded Interactionssupporting

confidence: 53%

Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study

Guo

Liang

Liu

et al. 2021

IJMS

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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), res (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.

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Section: Nonbonded Interactionssupporting

confidence: 53%

Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study

Guo

Liang

Liu

et al. 2021

IJMS

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“…Notably, after the 100 ns MD simulation, a decrement in the Δ G Bind Solv GB was noted and no substantial difference was observed in the Δ G Bind Lipo energy terms. Similar energy dissociation components were previously noted to contribute to the stability of the docked complexes of the PD-L1 protein [ 79 , 80 ]. Furthermore, reduction in net ligand strain energy was also noted following 100 ns MD simulation in each complex in comparison to the respective docked poses, suggesting the favorable contribution to the protein–ligand complex stability after 100 ns MD simulation ( Figure 7 ).…”

Section: Resultssupporting

confidence: 73%

Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy

Kumar

Moustafa

Sahoo

et al. 2022

Life

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Several therapeutic monoclonal antibodies approved by the FDA are available against the PD-1/PD-L1 (programmed death 1/programmed death ligand 1) immune checkpoint axis, which has been an unprecedented success in cancer treatment. However, existing therapeutics against PD-L1, including small molecule inhibitors, have certain drawbacks such as high cost and drug resistance that challenge the currently available anti-PD-L1 therapy. Therefore, this study presents the screening of 32,552 compounds from the Natural Product Atlas database against PD-L1, including three steps of structure-based virtual screening followed by binding free energy to refine the ideal conformation of potent PD-L1 inhibitors. Subsequently, five natural compounds, i.e., Neoenactin B1, Actinofuranone I, Cosmosporin, Ganocapenoid A, and 3-[3-hydroxy-4-(3-methylbut-2-enyl)phenyl]-5-(4-hydroxybenzyl)-4-methyldihydrofuran-2(3H)-one, were collected based on the ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and binding free energy (>−60 kcal/mol) for further computational investigation in comparison to co-crystallized ligand, i.e., JQT inhibitor. Based on interaction mapping, explicit 100 ns molecular dynamics simulation, and end-point binding free energy calculations, the selected natural compounds were marked for substantial stability with PD-L1 via intermolecular interactions (hydrogen and hydrophobic) with essential residues in comparison to the JQT inhibitor. Collectively, the calculated results advocate the selected natural compounds as the putative potent inhibitors of PD-L1 and, therefore, can be considered for further development of PD-L1 immune checkpoint inhibitors in cancer immunotherapy.

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“…Zhong et al generated a pharmacophore model based on BMS small molecule inhibitors, which consisted of one hydrogen bond donor, three hydrophobic points, and one positive ionizable point, and identified residues of PD-L1: Ile54, Tyr56, Val68, Met115, and Ala121 were involved in generating hydrophobic interactions, and Asp122 and Lys124 were involved in forming hydrogen bonds [ 33 ]. Guo et al investigated the inhibitory mechanism of PD-L1 dimer/BMS-200-related small molecule inhibitors by molecular dynamics simulation [ 34 ]. It was found that the inhibitors mainly bound to the key residues Ile54, Tyr56, Met115, Ala121, and Tyr123 on the PD-L1 dimer with non-polar interactions, and induced conformational changes in key residues.…”

Section: Introductionmentioning

confidence: 99%

Approaching the Dimerization Mechanism of Small Molecule Inhibitors Targeting PD-L1 with Molecular Simulation

Liang

Wang

Yang

et al. 2023

IJMS

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Inhibitors blocking the PD-1/PD-L1 immune checkpoint demonstrate impressive anti-tumor immunity, and small molecule inhibitors disclosed by the Bristol-Myers Squibb (BMS) company have become a hot topic. In this work, by modifying the carbonyl group of BMS-202 into a hydroxyl group to achieve two enantiomers (MS and MR) with a chiral center, we found that this is an effective way to regulate its hydrophobicity and thus to reduce the negative effect of polar solvation free energy, which enhances the stability of PD-L1 dimer/inhibitor complexes. Moreover, we studied the binding modes of BMS-200 and BMS-202-related small molecule inhibitors by molecular dynamics simulation to explore their inhibitory mechanism targeting PD-L1 dimerization. The results showed that the size exclusion effect of the inhibitors triggered the rearrangement of the residue ATyr56, leading to the formation of an axisymmetric tunnel-shaped pocket, which is an important structural basis for improving the binding affinity of symmetric inhibitors with PD-L1. Furthermore, after inhibitor dissociation, the conformation of ATyr123 and BMet115 rearranged, which blocked the entrance of the binding pocket, while the reverse rearrangements of the same residues occurred when the PD-L1 monomer was complexed with the inhibitors, preparing PD-L1 for dimerization. Overall, this study casts a new light on the inhibitory mechanism of BMS inhibitors targeting PD-L1 dimerization and provides an idea for designing novel small molecule inhibitors for future cancer immunotherapy.

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

Cited by 27 publications

References 62 publications

Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study

Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study

Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy

Approaching the Dimerization Mechanism of Small Molecule Inhibitors Targeting PD-L1 with Molecular Simulation

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