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

Danfeng Shi,Shuangyan Zhou,Zhitong Bing,Huanxiang Liu,Xiaoli An,Xiaojun Yao,Qifeng Bai

doi:10.3389/fchem.2019.00764

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.

Highlights

The blockage of the protein-protein interaction (PPI) between programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) can reactivate the effector functions of T cell and eliminate tumor phenotypes with significant PDL1 expression (Gatalica et al, 2014; Patel and Kurzrock, 2015; Sharma and Allison, 2015a,b)
In order to explore the interactive process of Bristol-Myers Squibb (BMS) small-molecule inhibitors, we constructed two kinds of ligand-bound PD-L1 monomer systems as shown in Figure 1 and used molecular dynamics simulations to evaluate the stabilities of both binding modes by two replicas
The BMS small-molecule inhibitors tended to interact with one PD-L1 monomer first and further formed dimer with the other monomer for an advantage of stability

Summary

Introduction

The blockage of the protein-protein interaction (PPI) between programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) can reactivate the effector functions of T cell and eliminate tumor phenotypes with significant PDL1 expression (Gatalica et al, 2014; Patel and Kurzrock, 2015; Sharma and Allison, 2015a,b). The crystal structures of PD1/PD-L1 complex revealed the interface and hot-spot domains for both proteins (Zak et al, 2015; Pascolutti et al, 2016), which provided the structural basis for drug design Ligands such as monoclonal antibodies (mAbs) (Lee et al, 2016, 2017; Liu K. et al, 2016; Tan et al, 2017; Zhang et al, 2017a,b), peptides (Chang et al, 2015; Magiera-Mularz et al, 2017), and small-molecule compounds (Abdel-Magid, 2015; Zak et al, 2016; Skalniak et al, 2017) had been discovered to interact with the PPI interface of PD-1 or PD-L1, showed obvious inhibitory activities against PD-1/PD-L1 signaling pathways.

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