Is the Triggering of PD-L1 Dimerization a Potential Mechanism for Food-Derived Small Molecules in Cancer Immunotherapy? A Study by Molecular Dynamics

Abstract

Using small molecules to inhibit the PD-1/PD-L1 pathway is an important approach in cancer immunotherapy. Natural compounds such as capsaicin, zucapsaicin, 6-gingerol and curcumin have been proposed to have anticancer immunologic functions by downregulating the PD-L1 expression. PD-L1 dimerization promoted by small molecules was recently reported to be a potential mechanism to inhibit the PD-1/PD-L1 pathway. To clarify the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and molecular dynamics simulations were performed. The results evidenced that these compounds could inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. Binding free energy calculations showed that capsaicin, zucapsaicin, 6-gingerol and curcumin have strong binding ability with the PD-L1 dimer, where the affinities of them follow the trend of zucapsaicin > capsaicin > 6-gingerol ≈ curcumin. Analysis by residue energy decomposition, contact numbers and nonbonded interactions revealed that these compounds have a tight interaction with the C-sheet, F-sheet and G-sheet fragments of the PD-L1 dimer, which were also involved in the interactions with PD-1. Moreover, non-polar interactions between these compounds and the key residues Ile54, Tyr56, Met115 and Ala121 play a key role in stabilizing the protein–ligand complexes in solution, in which the 4′-hydroxy-3′-methoxyphenyl group and the carbonyl group of zucapsaicin, capsaicin, 6-ginger and curcumin were significant for the complexation of small molecules with the PD-L1 dimer. The conformational variations of these complexes were further analyzed by free energy landscape (FEL) and principal component analysis (PCA) and showed that these small molecules could make the structure of dimers more stable. This work provides a mechanism insight for food-derived small molecules blocking the PD-1/PD-L1 pathway via directly targeting the PD-L1 dimerization and offers theoretical guidance to discover more effective small molecular drugs in cancer immunotherapy.

Garcinia mangostana L. Pericarp Extract and Its Active Compound α-Mangostin as Potential Inhibitors of Immune Checkpoint Programmed Death Ligand-1

“…The result suggested that the high flexibility of A Tyr56 allowed αmangostin to interact with both forms of Tyr56 after 100 ns simulation. Molecular dynamics study of the natural bioactive compounds capsaicin, zucapsaicin, 6-gingerol, and curcumin with the PD-L1 dimer revealed that the key residues Ile54, Tyr56, Met115, and Ala121 play a role in stabilizing protein-ligand complexes [38]. This study also revealed that Tyr56, Met115, and Ala121 were key residues for ligand binding.…”

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

“…PD-L1 can form homodimers and tetramers, and its complex glycosylation is linked to the homodimeric structure of its intracellular domain [ 190 ]. Natural compounds such as capsaicin, 6-gingerol, and curcumin may block the PD-1/PD-L1 interaction by targeting PD-L1 dimerization, enhancing anticancer immunity [ 191 ]. The small molecule BMS-202, with modified carbonyl to hydroxyl groups, produces two enantiomers, MS and MR, both of which disrupt PD-L1 function by targeting its dimerization [ 192 ].…”

“…Su et al introduced carbon-based PROTACs (CDTACs), which also target PD-L1 but for proteasome degradation, showing promise in preclinical studies by inhibiting tumor growth and boosting the immune response [165]. Sun et al [190,191] Table 1 Targeting posttranslational modifications of PD-1/PD-L1 developed ROTACs, a type of PROTAC that targets and degrades specific signaling molecules, using a chimera called R2PD1 to efficiently degrade PD-L1 in melanoma cells, outperforming existing treatments in activating immune responses and inhibiting tumor growth [166]. These developments suggest that PROTACs could significantly improve PD-1/PD-L1-targeted therapies for cancer [167].…”