Computational analysis of hot spots and binding mechanism in the PD-1/PD-L1 interaction

Huang, Dading; Wen, Wei; Liu, Xiao; Li, Yang; Zhang, John Z. H.

doi:10.1039/c9ra01369e

Cited by 24 publications

(13 citation statements)

References 80 publications

(109 reference statements)

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“…The residues of the C, F and G regions fluctuated more in the dimer state (~2.0 Å) than in bound states (<2 Å), meaning that upon binding of BMS-200-related molecules, the domains showed more stable behavior. Our results agree with those of the literature, suggesting that sheet domains on the PD-L1 dimer are critical for the binding of small molecules and that the regions undergo significant conformational change [ 27 , 34 ]. In addition, when compared with the S system, more obvious fluctuations could be observed in the C”D loop of A PD-L1 and the BC loop of B PD-L1 in the R system, implying that the latter has enhanced flexibility, which was also coincident with the RMSD values.…”

Section: Resultssupporting

confidence: 92%

“…Combinations of molecular modeling tools, such as molecular docking, molecular dynamics (MD) simulation and the molecular mechanics–Poisson Bolzmann surface area (MM-PBSA) approach [ 22 ], offer us a unique opportunity to construct protein–small-molecule antagonist systems [ 23 , 24 ], analyze recognition mechanisms [ 25 ] and recognize key residues at binding pockets [ 25 , 26 ]. Recently, Huang et al [ 27 ] predicted the hotspots in the PD-1/PD-L1 pathway and highlighted the importance of polar and nonpolar interactions between PD-1 and PD-L1 by MD simulations and binding free energy calculations. Ahmed et al [ 28 ] evaluated the dynamic characteristics of small-molecule binding regions on PD-L1, emphasizing the specific flexible domains at the PD-L1 surface and the key role of methionine residue for binding.…”

Section: Introductionmentioning

confidence: 99%

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

Guo

Jin

Wang

et al. 2021

IJMS

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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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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

Guo

Jin

Wang

et al. 2021

IJMS

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“…In the PD-1:PD-L1 interface, hot region containing hydrophobic regions are involved in hotspots 1 and 2 and are proposed to be ideal for binding to PD-L1 using conventional small molecules. Hotspots in the PD1:PD-L interaction have also been quantitatively predicted based on the theoretical calculations ( 36 ). This analysis has identified six hot spots on PD-L1 (Tyr123, Tyr56, Arg125, Met115, Arg113, and Gln66) and two warm spots on PD-L1 (Ile54 and Lys124) ( 36 ).…”

Section: Considerations For Targeting Pd-1 Signaling Pathway Using Sm...mentioning

confidence: 89%

“…Hotspots in the PD1:PD-L interaction have also been quantitatively predicted based on the theoretical calculations ( 36 ). This analysis has identified six hot spots on PD-L1 (Tyr123, Tyr56, Arg125, Met115, Arg113, and Gln66) and two warm spots on PD-L1 (Ile54 and Lys124) ( 36 ). Among various hotspots/hot regions reported, the hydrophilic hot region containing polar residues is reported to be a solvent exposed with extended shallow groove and with multiple hydrogen bond donors and acceptors and is considered to be challenging to target via conventional small molecules abiding the famous rule of five ( 37 ).…”

Section: Considerations For Targeting Pd-1 Signaling Pathway Using Sm...mentioning

confidence: 89%

Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development

Sasikumar

Ramachandra

2022

Front. Immunol.

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Pioneering success of antibodies targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has changed the outlook of cancer therapy. Although these antibodies show impressive durable clinical activity, low response rates and immune-related adverse events are becoming increasingly evident in antibody-based approaches. For further strides in cancer immunotherapy, novel treatment strategies including combination therapies and alternate therapeutic modalities are highly warranted. Towards this discovery and development of small molecule, checkpoint inhibitors are actively being pursued, and the efforts have culminated in the ongoing clinical testing of orally bioavailable checkpoint inhibitors. This review focuses on the small molecule agents targeting PD-1 checkpoint pathway for cancer immunotherapy and highlights various chemotypes/scaffolds and their characterization including binding and functionality along with reported mechanism of action. The learnings from the ongoing small molecule clinical trials and crucial points to be considered for their clinical development are also discussed.

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“…The prediction of residues crucial for the formation of favorable protein-ligand or protein-protein interactions is an asset in the field of rational drug design. These decisive sets of amino acids are called ‘hotspots’ and numerous studies with the objective of quantifying the contribution of residues towards binding affinity have been conducted to facilitate precise identification of ‘hotspot’ residues [ 73 , 74 , 75 , 76 , 77 ]. Experimentally, the determination of ‘hotspots’ proceeds through traditional methods such as alanine scanning mutagenesis, structure-activity relationship by NMR and multiple solvent crystal structures (MSCS) [ 78 , 79 , 80 ].…”

Section: Computational Methods For the Prediction Of Protein-protementioning

confidence: 99%

Advances in Molecular Dynamics Simulations and Enhanced Sampling Methods for the Study of Protein Systems

Lazim

Suh

Choi

2020

IJMS

118

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Molecular dynamics (MD) simulation is a rigorous theoretical tool that when used efficiently could provide reliable answers to questions pertaining to the structure-function relationship of proteins. Data collated from protein dynamics can be translated into useful statistics that can be exploited to sieve thermodynamics and kinetics crucial for the elucidation of mechanisms responsible for the modulation of biological processes such as protein-ligand binding and protein-protein association. Continuous modernization of simulation tools enables accurate prediction and characterization of the aforementioned mechanisms and these qualities are highly beneficial for the expedition of drug development when effectively applied to structure-based drug design (SBDD). In this review, current all-atom MD simulation methods, with focus on enhanced sampling techniques, utilized to examine protein structure, dynamics, and functions are discussed. This review will pivot around computer calculations of protein-ligand and protein-protein systems with applications to SBDD. In addition, we will also be highlighting limitations faced by current simulation tools as well as the improvements that have been made to ameliorate their efficiency.

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Computational analysis of hot spots and binding mechanism in the PD-1/PD-L1 interaction

Abstract: The hot spots quantitatively predicted by the recently developed MM/GBSA/IE method reveal a hydrophobic core in the PD-1/PD-L1 interaction.

Cited by 24 publications

References 80 publications

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

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

Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development

Advances in Molecular Dynamics Simulations and Enhanced Sampling Methods for the Study of Protein Systems

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