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

Abstract

Background 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 PD1(Programmed cell death 1)/PDL1(Programmed death-ligand 1), which activates T cells. In this work, the aim was to find high-affinity drugs against PDL1 using computational tools and conjugate them with nanoparticles. The cytotoxic activity of the drug-conjugated nanoparticles was then tested. Methods The screening of one hundred thousand 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. AgNPs and 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), 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). Results The top screened drugs were ZINC1098661 and three 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 methylthiazol tetrazolium (MTT) assay showed that conjugated AgNPs and AuNPs with Irinotecan had a high toxic effect on A549 cancer cell line than Imatinib conjugated with AgNPs and AuNPs. Conclusion: This study provides a promising avenue for further investigation and development of nanoparticle-drug conjugates as a potential cancer immunotherapy strategy.