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

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.

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.

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.

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.

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.