Title:In silico-driven identification of Pranlukast as a Stabilizer of PD-L1 Homodimers
Volume: 25
Issue: 3
Author(s): Luis Córdova-Bahena, Carlos Landero-Marín, Xcaret Flores-Hernández, Leonardo Daniel Alvarez-Coronel, Alexis Paulina Jiménez-Uribe, Nohemí Salinas-Jazmín, Zhiqiang An and Marco Velasco-Velázquez*
Affiliation:
- School of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, 04510, Mexico
- Texas Therapeutics Institute, Brown
Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, 77030, USA
Keywords:
Immune checkpoint, drug repurposing, virtual screening, pharmacophore modeling, molecular dynamics, pranlukast.
Abstract:
Introduction: Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1)
are critical immune checkpoints in cancer biology. Multiple small-molecule drugs have been developed as inhibitors
of the PD-1/PD-L1 axis. Those drugs promote the formation of PD-L1 homodimers, causing their stabilization,
internalization, and subsequent degradation. Drug repurposing is a strategy that expedites the clinical translation
by identifying new effects of drugs with clinical use. Herein, we aimed to repurpose drugs as inductors of
PD-L1 homodimerization and, therefore, as potential inhibitors of PD-L1.
Method: We generated a hybrid pharmacophore model by analyzing the structures of reported ligands that induce
PD-L1 homodimerization and their target-binding mode. Pharmacophore-matching compounds were selected
from a chemical library of Food and Drug Administration (FDA)-approved drugs. Their binding modes to PDL1
homodimers were assessed by molecular docking and the stability of the complexes and the corresponding
binding energies were evaluated by molecular dynamics (MD) simulations. Finally, the activity of one drug as
promoter of PD-L1 homodimerization was assessed in protein crosslinking assays.
Results:We identified 12 pharmacophore-matching compounds, but only 4 reproduced the binding mode of the
reference inhibitors. Further characterization by MD showed that pranlukast, an antagonist of leukotriene receptors
that is used to treat asthma, generated stable and energy-favorable interactions with PD-L1 homodimers and
induced homodimerization of recombinant PD-L1.
Conclusion: Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis, meriting its repurposing as an
antitumor drug.
