Molecular Modeling Studies on the Binding Mode of the PD-1/PD-L1 Complex Inhibitors

Almahmoud, Suliman A.; Zhong, Haizhen A.

doi:10.3390/ijms20184654

Cited by 35 publications

(22 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The three-dimensional structure of (S)-BMS-200 originated from PDB (ID: 5N2F, S-enantiomer). For (R)-BMS-200 and (MOD)-BMS-200, due to the lack of crystal parameters, their initial structures were first drawn in Gauss View 5.0 software [ 40 ] and then optimized to the minimized energy in Chem 3D software using the MM2 forcefield (see Figure 1 ) [ 16 ]. The missing parts of the PD-L1 structures were completed using the WHAT IF server.…”

Section: Computational Detailsmentioning

confidence: 99%

“…However, due to their high molecular weights, they possess several limitations, such as low steadiness and poor tumor-permeability profiles [ 13 , 15 ]. In comparison, small-molecule inhibitors (MW < 550 Da) can avoid these limitations and present a promising alternative way to disrupt the PD-1/PD-L1 axis [ 10 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…In terms of mAbs targeting this pathway, Sun et al [ 29 ] and Shi et al [ 30 ] claimed that the CC’FG area of PD-L1 is instrumental in the recognition of mAbs. In relation to small-molecule antagonists, molecular docking was applied by Almahmoud et al [ 16 ] to evaluate hotspot residues on the PD-L1 dimer, showing that the residues Tyr56, Asp122 and Lys124 have important functions upon binding with BMS ligands. Similar results were also obtained by Shi et al [ 31 ], who reported that the key residues on both PD-L1 monomers were Ile54, Tyr56, Met115, Ala121 and Tyr123.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Computational Detailsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…In other MD simulations the influence of mutations on ligand binding was examined [ 12 , 13 ]. Also the conformational dynamics of PD-L1 were studied with MD [ 14 , 15 ]. We have also performed preliminary investigations [ 16 ] which are supplemented in the current work.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab

2020

View full text Add to dashboard Cite

Background The immune checkpoint receptor programmed cell death protein I (PD-1) has been identified as a key target in immunotherapy. PD-1 reduces the risk of autoimmunity by inducing apoptosis in antigen-specific T cells upon interaction with programmed cell death protein ligand I (PD-L1). Various cancer types overexpress PD-L1 to evade the immune system by inducing apoptosis in tumor-specific CD8+ T cells. The clinically used blocking antibody nivolumab binds to PD-1 and inhibits the immunosuppressive interaction with PD-L1. Even though PD-1 is already used as a drug target, the exact mechanism of the receptor is still a matter of debate. For instance, it is hypothesized that the signal transduction is based on an active conformation of PD-1. Results Here we present the results of the first molecular dynamics simulations of PD-1 with a complete extracellular domain with a focus on the role of the BC-loop of PD-1 upon binding PD-L1 or nivolumab. We could demonstrate that the BC-loop can form three conformations. Nivolumab binds to the BC-loop according to the conformational selection model whereas PD-L1 induces allosterically a conformational change of the BC-loop. Conclusion Due to the structural differences of the BC-loop, a signal transduction based on active conformation cannot be ruled out. These findings will have an impact on drug design and will help to refine immunotherapy blocking antibodies.

show abstract

“…8 Programmed cell death-1 (PD-1) is an immune checkpoint inhibiting T-cell activation and effector T-cell function, and has been recognized as an important target for cancer immunotherapy. [9][10][11] PD-1 blockade can restore T-cell antitumor immunity through blocking the binding of PD-1 and its ligand PD-L1. 12,13 Many studies have shown the efficacy of immunotherapy in esophageal cancer.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of programmed cell death‐1 antibody SHR‐1210 combined with concurrent chemoradiotherapy to treat locally advanced esophageal squamous cell carcinoma: a study protocol for an exploratory single‐arm phase Ib trial

Wei

Guo

Zhang

et al. 2020

Precision Radiation Oncology

View full text Add to dashboard Cite

Objective Esophageal squamous cell carcinoma (ESCC) is the most common pathological pattern in China, with poor prognosis due to its early and frequent metastasis. Definitive concurrent chemoradiotherapy is the standard treatment for inoperable locally advanced ESCC. Studies have shown promising efficacy of immune‐checkpoint inhibitors in ESCC. This study explores the safety and efficacy of immunotherapy combined with definitive concurrent chemoradiotherapy for locally advanced ESCC. Method This study was an exploratory, open, single‐arm clinical trial involving 20 untreated patients with locally advanced ESCC. The patients were treated with eight cycles (4 weeks per cycle) of SHR‐1210 concurrently combined with 6 weeks of radiotherapy, and 4 weeks of chemotherapy and apatinib beginning from 4 weeks after the completion of radiotherapy to the end of treatment. Primary end‐points were treatment‐related adverse events, serious adverse events, and patients’ quality of life (European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire (QLQ)‐C30 and QLQ‐OES18). Secondary end‐points were the objective response rate, progression‐free survival, and overall survival. Discussion This phase Ib study evaluates the tolerability and efficacy of programmed cell death‐1 antibody along with definitive concurrent chemoradiotherapy in treating locally advanced ESCC. This novel combination is expected to yield fewer side‐effects and better survival.

show abstract

Molecular Modeling Studies on the Binding Mode of the PD-1/PD-L1 Complex Inhibitors

Cited by 35 publications

References 60 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

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab

Safety and efficacy of programmed cell death‐1 antibody SHR‐1210 combined with concurrent chemoradiotherapy to treat locally advanced esophageal squamous cell carcinoma: a study protocol for an exploratory single‐arm phase Ib trial

Contact Info

Product

Resources

About