Computational identification of PDL1 inhibitors and their cytotoxic effects with silver and gold nanoparticles

Area of Science:

• Computational drug discovery
• Nanotechnology in medicine
• Cancer immunotherapy

Background:

• Immunotherapy enhances the immune system's response to cancer by targeting immune checkpoints like Programmed cell death protein 1/Programmed death-ligand 1 (PD1/PDL1).
• Developing novel therapeutic agents with high affinity for PDL1 is crucial for advancing cancer immunotherapy strategies.

Purpose of the Study:

• To identify high-affinity drug candidates against PDL1 using computational screening.
• To synthesize and characterize silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs).
• To conjugate selected drugs with nanoparticles and evaluate their cytotoxic activity against cancer cells.

Main Methods:

• Computational screening of 100,000 drugs from the ZINC database and FDA-approved drugs for PDL1 binding affinity.
• Physicochemical and toxicity analyses using SwissADME and ProTox-II.
• Synthesis of AgNPs and AuNPs using plant extracts, followed by characterization (UV-Vis, XRD, FTIR) and drug conjugation confirmation (UV-Vis, FTIR, DLS).
• Molecular docking and dynamics simulations to assess binding affinity and stability of drug-PDL1 complexes.
• Methylthiazol tetrazolium (MTT) assay to determine the cytotoxic effect of nanoparticle-drug conjugates on A549 cancer cell lines.

Main Results:

• Computational screening identified ZINC1098661, Irinotecan, Imatinib, and Methotrexate as top drug candidates.
• Docking studies indicated Irinotecan exhibited the highest binding affinity to PDL1 when conjugated with AgNPs and AuNPs.
• Molecular dynamics simulations confirmed the stability of the Irinotecan-PDL1 complex.
• MTT assays demonstrated that Irinotecan conjugated with AgNPs and AuNPs exhibited significantly higher cytotoxicity against A549 cells compared to Imatinib conjugates.

Conclusions:

• The study successfully identified potent PDL1 inhibitors and developed nanoparticle-drug conjugates with enhanced anti-cancer activity.
• Irinotecan-conjugated nanoparticles show significant promise as a novel strategy for cancer immunotherapy.
• Further investigation into these nanoparticle-drug conjugates could lead to the development of more effective cancer treatments.