Structure-based small inhibitors search combined with molecular dynamics driven energies for human programmed cell death-1 (PD-1) protein

Abstract

Human immune system is specialized in distinguishing normal cells from foreign particles mainly through proteins expressed on immune cells called ‘checkpoints’. Immune checkpoints work as a switch to activate and deactivate immune responses. T cells express one of the immune checkpoint, human programmed cell death-1 (PD-1), which normally operates as an off-switch function to protect the normal cell from T-cell attack. Binding of PD-1 to its ligand, the programmed cell death ligand (PD-L1/2) expressed on myeloid/cancer cells, induce downstream inhibitory signals, leading to tumor immune evasion. Targeting PD-1 or PD-L1 can boost the immune response against cancer cells. To design novel small molecule inhibitors for the PD-1, in silico structure-based screening on pharmacophoric points and molecular docking were performed. Based on the docking score and significant binding interaction with the crucial residues of PD-1 (Thr59, Glu61, Ser62, Glu84, Arg86 and Ala132), compounds were selected from the ZINC20 database, and their dynamic behavior and conformational stability were examined through molecular dynamic simulations. Besides, the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method was used to calculate the binding strength of each selected inhibitor complexed with PD-1. The binding energy calculations revealed that these selected inhibitors show a considerable affinity for PD-1. The selected novel inhibitors exhibit excellent drug-like and pharmacokinetic properties (absorption, distribution, metabolism, excretion and toxicity). In conclusion, the identified novel compounds (ZINC1443480030, ZINC1002854123, ZINC988238128, ZINC1481242350, ZINC1001739421, ZINC1220816434 and ZINC1167786692) from the current study can be validated in-vitro as potential PD-1 inhibitors and for discovery of novel drugs against PD-1 in the future.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human programmed cell death-1 (PD-1)
• pharmacophore modeling
• structure-based virtual screening
• molecular dynamic simulation

Acknowledgments

The authors would like to thank the University of Nizwa for their generous support of this project. We thank the technical staff for their assistance.

Authors’ contributions

AK, EE and AAH conceived and designed the study. MW, AA and SAH performed experiments. MW and SAH analyzed the data. MW, SAH and AK wrote the manuscript with inputs and comments from all co-authors. All authors have read and approved the final version of the manuscript.

Disclosure statement

The authors declare that they have no competing interests.

Availability of data and materials

All datasets on which the conclusions of the manuscript rely are presented in the paper.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.