Identification of new small molecule inhibitors of PD-1/PD-L1 interaction by a comprehensive ligand fishing system

  • J Pharm Biomed Anal. 2025 Nov 23:270:117281. doi: 10.1016/j.jpba.2025.117281.
Dongyao Wang  1 ,  Ying Zhang  2 ,  Dan Li  3 ,  Ningqi Xia  2 ,  Xiaofei Wang  2 ,  Xiaofei Chen  4 ,  Bin Lu  2 ,  Diya Lv  5 ,  Yan Cao  6
Affiliations
  • 1. Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
  • 2. Department of Biochemical Pharmacy, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
  • 3. Eastern Hepatobiliary Surgery Institute, Naval Medical University, Shanghai 200433, China.
  • 4. Center for Instrumental Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
  • 5. Center for Instrumental Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China. Electronic address: [email protected].
  • 6. Department of Biochemical Pharmacy, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Naval Medical University, Shanghai 200433, China. Electronic address: [email protected].
PMID: 41308584 DOI: 10.1016/j.jpba.2025.117281
Abstract

The development of programmed death 1 (PD-1) checkpoint/programmed death-ligand 1 (PD-L1) interaction inhibitors has opened a new front in the treatment of carcinoma. An increasing amount of research is devoted to small-molecule compounds that target this PD-1/PD-L1 interaction. In this article, we report the discovery of three new PD-1/PD-L1 inhibitors from Scutellaria baicalensis Georgi and Sophora flavescens Aiton herbal extracts, namely baicalin, maackiain, and oxysophocarpine, using a comprehensive ligand fishing system, which integrates a dual-target surface plasmon resonance biosensor and a Magnetic Beads method. These three compounds were also confirmed in the serum in vivo, validated by binding affinity evaluation, molecular docking, and competitive enzyme-linked immunosorbent assay (ELISA) assay to act upon the interface of PD-1/PD-L1. Thus, these three ingredients could be potential PD-1/PD-L1 inhibitors and may serve as hit compounds for immunotherapeutic drug discovery. These results also highlight the efficiency of the dual-target surface plasmon resonance (SPR) and Magnetic Beads ligand fishing system in drug screening for disease treatment.

Keywords
Herbal extracts; Magnetic beads; PD-1/PD-L1 interactions; Screening; Surface plasmon resonance biosensor.
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