Abstract

Background:
Globally, cancer is a major burden of disease threatening human health. To date, immune checkpoint inhibitors are monoclonal antibodies that cover various cancer indications as monotherapy or in combination, have revealed remarkable clinical success in a wide range of solid tumors and hematologic malignancies.

Aim:
Due to the inherent limitations of antibodies, it is reasonable to consider discovering orally bioavailable small molecule inhibitors that target programmed cell death protein 1/programmable death-ligand 1 (PD-1/PD-L1) signaling pathway as alternative. Discovering a new therapeutic drug is a complex, costly and lengthy process.

Methods: A combination of computational methods is an excellent replacement to identify potential drug candidates from the large compound libraries. In the study, 30 hit compounds were initially retrieved by pharmacophore-based virtual screening. Thereafter, 5 compounds with lowest Gibb’s free energy (ΔG) values, namely ZINC85867378, ZINC16267039, ZINC64219346, ZINC68604154 and ZINC20576138, have been chosen
for further evaluation.

Results:
This study establishes the workflow combining pharmacophore virtual screening, molecular docking, and absorption, distribution, metabolism, excretion - toxicity (ADMET) prediction to identify possible small molecules that can interact with PD-1.

Conclusion:
The identified compounds might serve as starting points to design potential safe and efficacious molecules in cancer Immunotherapy. Further evaluation through in vitro and in vivo is necessary to optimize drug properties.

Key words: PD-1; Small molecule inhibitors; Cancer immunotherapy; Immune checkpoints; Computeraided drug design.