Leveraging structural and 2D-QSAR to investigate the role of functional group substitutions, conserved surface residues and desolvation in triggering the small molecule-induced dimerization of hPD-L1

Abstract

Small molecules are rising as a new generation of immune checkpoints’ inhibitors, with compounds targeting the human Programmed death-ligand 1 (hPD-L1) protein are pioneering this area of research. Promising examples include the recently disclosed compounds from Bristol-Myers-Squibb (BMS). These molecules bind specifically to hPD-L1 through a unique mode of action. They induce dimerization between two hPD-L1 monomers through the hPD-1 binding interface in each monomer, thereby inhibiting the PD-1/PD-L1 axis. While the recently reported crystal structures of such small molecules bound to hPD-L1 reveal valuable insights regarding their molecular interactions, there is still limited information about the dynamics driving this unusual complex formation. The current study provides an in-depth computational structural analysis to study the interactions of five small molecule compounds in complex with hPD-L1. By employing a combination of molecular dynamic simulations, binding energy calculations and computational solvent mapping techniques, our analyses quantified the dynamic roles of different hydrophilic and lipophilic residues at the surface of hPD-L1 in mediating these interactions. Furthermore, ligand-based analyses, including Free-Wilson 2D-QSAR was conducted to quantify the impact of R-group substitutions at different sites of the phenoxy-methyl biphenyl core. Our results emphasize the importance of a terminal phenyl ring that must be present in any hPD-L1 small molecule inhibitor. This phenyl moiety overlaps with a very unfavorable hydration site, which can explain the ability of such small molecules to trigger hPD-L1 dimerization.

Theoretical and experimental studies on the interaction of biphenyl ligands with human and murine PD-L1: Up-to-date clues for drug design

“…An important role is played by the contacts that the small molecule inhibitor can establish with both Tyr56 and Tyr123 which can, in turn, influence the interaction network required for the hPD-L1 dimer stabilization. We also underline that tight hPD-L1 inter-chain contacts would hamper the ligand access to the binding site in a pre-existing protein dimer, in line with the hypothesis that a small molecule inhibitor would first bind to a hPD-L1 monomer and then interact with a second monomer to form a stable dimer complex [98] .…”

A Comprehensive Computational Insight into the PD-L1 Binding to PD-1 and Small Molecules

“…The computational solvent mapping suggests that BMS ligand to PD-L1 monomer can be favored by the displacement of unfavorable water molecules from their highly energetic hydration site. This result suggests that substitution of the A ring can further contribute to this effect [ 86 ].…”