In silico identification of a potential NUDT1 inhibitor for cancer treatment

NUDIX Hydrolase 1 (NUDT1) plays a pivotal role in the survival of cancer cells by hydrolyzing the Oxidative nucleotide species such as 8-oxo-dGTP, which inhibits the oxidative DNA damage resulting in tumor progression. Due to its overexpression in various malignancies, it is identified as a promising therapeutic target for anticancer drug design. In this study, we conducted a ligand-based computational screening of 1574 compounds sourced from the Natural Product Activity & Species Source Database (NPACT), IIT Delhi, using PyRx. From the initial screening, the top five compounds with the highest binding affinity were selected for further ADMET (absorption, distribution, metabolism, excretion, and toxicity) and Toxicity analysis. Among these, ROPA (NPACT00071) was chosen for its favorable drug likeness. However, due to a formatting issue in the pdbqt representation, structural correction was needed. Following structural correction, a rationally designed hydroxyl-substituted derivative was generated and further optimized through QSAR-guided structure–activity relationship analysis, which identified Structure 1 as the most promising lead for subsequent computational evaluation. It was then docked again against NUDT1, resulting in a binding affinity of -12.6 Kcal/mol. ADMET analysis and toxicity profiling via SwissADME and ProTox-3.0 confirmed the new derivative’s favorable drug-likeness properties. To further evaluate its stability with NUDT1, a 200ns molecular dynamics simulation was performed using GROMACS 2022. Additionally, DFT calculations (B3LYP/6–31 G(d, p)) were performed using Gaussian, indicating favorable molecular orbital energies and electronic stability. These findings suggest that the optimized new derivative is a promising computationally prioritized lead scaffold for future experimental evaluation as a NUDT1 inhibitor.