Computational design, synthesis, and in vitro evaluation of thiadiazole-derived PARP-1 inhibitors

Background Poly (ADP-ribose) polymerase-1 (PARP-1) is a crucial enzyme in DNA repair pathways and a significant target for cancer therapy. Due to their favorable physicochemical and biological characteristics, heterocyclic scaffolds like 1,3,4-thiadiazoles are good candidates for PARP-1 inhibitor design.Objectives The purpose of this work was to use an integrated computational and experimental strategy to design, manufacture, and assess new 1,3,4-thiadiazole derivatives as possible PARP-1 inhibitors.Methods MM-GBSA binding-energy calculations and molecular docking were used to create and screen a library of 1,3,4-thiadiazole analogues. Redocking the co-crystallized ligand confirmed the accuracy of the docking, resulting in an RMSD of 0.0000 Å. To evaluate drug-likeness and oral absorption characteristics, ADME predictions were made. The dynamic stability of the PARP-1–D1 complex was assessed using a 100-ns molecular dynamics simulation. The MTT assay was used to assess the in vitro cytotoxicity of the chosen compounds against MCF-7 cell lines.Results Computational studies identified C10, D1, and E10 as the most promising PARP-1 inhibitors, showing strong binding through hydrophobic interactions, hydrogen bonds, and π–π stacking with key residues such as ARG878, ALA880, GLY894, TYR896, and SER864. ADME analysis indicated good physicochemical properties and oral availability. MD simulations confirmed the stability of the PARP-1–D1 complex. In vitro studies further validated their strong antiproliferative activity against MCF-7 cells.Conclusion The combined computational and experimental results show that C10, D1, and E10 are promising lead scaffolds for the creation of new anticancer drugs that target PARP-1.