Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

Abstract

Recently, small-molecule compounds have been reported to block the PD-1/PD-L1 interaction by inducing the dimerization of PD-L1. All these inhibitors had a common scaffold and interacted with the cavity formed by two PD-L1 monomers. This special interactive mode provided clues for the structure-based drug design, however, also showed limitations for the discovery of small-molecule inhibitors with new scaffolds. In this study, we revealed the structure-activity relationship of the current small-molecule inhibitors targeting dimerization of PD-L1 by predicting their binding and unbinding mechanism via conventional molecular dynamics and metadynamics simulation. During the binding process, the representative inhibitors (BMS-8 and BMS-1166) tended to have a more stable binding mode with one PD-L1 monomer than the other and the small-molecule inducing PD-L1 dimerization was further stabilized by the non-polar interaction of Ile54, Tyr56, Met115, Ala121, and Tyr123 on both monomers and the water bridges involved in ALys124. The unbinding process prediction showed that the PD-L1 dimerization kept stable upon the dissociation of ligands. It's indicated that the formation and stability of the small-molecule inducing PD-L1 dimerization was the key factor for the inhibitory activities of these ligands. The contact analysis, R-group based quantitative structure-activity relationship (QSAR) analysis and molecular docking further suggested that each attachment point on the core scaffold of ligands had a specific preference for pharmacophore elements when improving the inhibitory activities by structural modifications. Taken together, the results in this study could guide the structural optimization and the further discovery of novel small-molecule inhibitors targeting PD-L1.

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

“…PD-L1 is highly glycosylated, and N-linked glycosylation of PD-L1 critically maintains its protein stability and is required for its interaction with PD-1 to efficiently suppress T-cell activity. Recently, Bristol-Myers Squibb (BMS)-developed compounds with a common (2-methyl-4-biphenylyl)methanol scaffold have been reported to block the PD-1/PD-L1 interaction by interacting with the cavity formed by the two PD-L1 monomers and inducing the dimerization of PD-L1 [71][72][73][74][75][76][77]. Structural studies have revealed a dimeric protein complex with a single small molecule that stabilizes the dimer and thereby occludes the PD-1 interaction surface of PD-L1.…”

“…Computer-aided docking/MD simulations predicted the ability of RSV to locate at the center of the PD-L1 homodimer, filling a deep hydrophobic pocket that contributes multiple additional interactions between the PD-L1 monomers. Indeed, RSV was predicted to almost perfectly occupy the target space of Bristol-Myers Squibb (BMS)developed nonpeptidic chemical inhibitors such as BMS-8, BMS-202, or BMS-1166, which have a common scaffold and interact with the cavity formed by two PD-L1 monomers, (consisting of Ile54, Tyr56, Met115, Ile116, Ala121, and Tyr123 [71,77]), thereby blocking the PD-1/PD-L1 interaction by inducing PD-L1dimerization. The double-strike PD-1/PD-L1 immune checkpoint inhibitor-like behavior of RSV based on its ability to directly target PD-L1 either via key post-translational modifications such as N-linked glycosylation [110][111][112][113][114] or via direct binding to PD-L1 to block PD-1 binding [71][72][73][74][75][76][77] interferes with PD-L1 stability and trafficking, impedes the correct targeting of PD-L1 to the cancer cell plasma membrane, and lastly elicits considerably enhanced cytotoxic T-lymphocyte immune-surveillance against tumor cells ( Figure 9).…”

“…The strong exacerbation of the cytotoxic activity of Tcells against RSV-treated cancer cells raised the suspicion that additional PD-L1-targeted RSV mechanisms of action might be involved. We speculated that such non-mutually exclusive mechanisms might involve RSV binding to the dimerization surface of PD-L1, which is the same employed by PD-L1 to interact with PD-L1 [71][72][73][74][75][76][77]. Computer-aided docking/MD simulations predicted the capacity of RSV to occupy the cavity formed by two PD-L1 monomers (ΔG=-9.252 kcal/mol) in a manner closely mimicking that of BMS-202 (ΔG=-11.11 kcal/mol), a small-molecule capable of inhibiting the PD-1/PD-L1 interaction by inducing PD-L1 dimerization through the PD-1 interacting surface AGING [71,75] (Figure 8, top).…”

Nanotechnologies for enhancing cancer immunotherapy

“…Small molecule inhibitors, whose scaffold is based on a substituted biphenyl compound connected to another aromatic ring via a benzyl ether bond, are mainly developed by Bristol-Myers Squibb (BMS) company [201]. In particular, compounds with (2-methyl-3-biphenyl) methanol scaffolds can induce PD-L1 dimerization and interact with hydrophobic channels formed by two PD-L1 monomers to inhibit PD-1/ PD-L1 pathway and then to alleviate exhaustion of T-cells [202,203]. They may be used as complementary or alternative treatments to overcome some of the shortcomings of mAb therapeutics.…”

Partial Least-Squares Discriminant Analysis and Ensemble-Based Flexible Docking of PD-1/PD-L1 Inhibitors: A Pilot Study

“…Remarkably, the compound NSC149050 with a relatively low molecular weight can still exhibit ∼50% inhibition at 25 μM test concentration. Shi et al 18 performed R group-based quantitative structure–activity relationship studies on 110 PD-L1 inhibitors from the patents of Bristol Myers Squibb (BMS) company. These inhibitors shared a common 2-methyl-3-(phenoxymethyl)-1,1′-biphenyl scaffold and were proved to block the PD-1/PD-L1 interaction by inducing the dimerization of PD-L1.…”