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

Abstract

Immunotherapy is a promising treatment for cancer that aims to boost the immune system’s response to cancer cells. This can be achieved by blocking Programmed cell death protein 1/Programmed death-ligand 1 (PD1/PDL1), which activates T cells. In this work, the aim was to find high-affinity drugs against PDL1 using computational tools and conjugate nanoparticles with them. The cytotoxic activity of the nanoparticle conjugated drugs was then tested. The screening of 100,000 drugs from the ZINC database and FDA-approved drugs was done computationally. The physicochemical properties and toxicity of the drugs were analyzed using SwissADME and ProTox-II, respectively. Silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) were synthesized using extracts of Catharanthus roseus flowers and Juglans regia shells, respectively. The characterization of AgNPs and AuNPs was performed using UV–Vis spectroscopy, X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Their conjugation with the drugs Irinotecan, Imatinib, and Methotrexate was also confirmed using UV–Vis, FTIR, and Dynamic light scattering (DLS). The top screened drugs were ZINC1098661 and 3 FDA-approved drugs (Irinotecan, Imatinib, and Methotrexate). Docking studies revealed that Irinotecan had the highest binding affinity towards PDL1 when conjugated with silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs). The Irinotecan-PDL1 complex was confirmed as the most stable through molecular dynamics simulations. The result of the methylthiazol tetrazolium (MTT) assay showed that conjugated AgNPs and AuNPs with Irinotecan had a higher toxic effect on the A549 cancer cell line than AgNPs and AuNPs conjugated with Imatinib. This study provides a promising avenue for further investigation and development of nanoparticle-drug conjugates as a potential cancer immunotherapy strategy. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-77868-8.