Structure-guided identification of potential MTH1 inhibitors from natural compounds: toward therapeutic targeting of oxidative DNA damage in cancer

Abstract

Disrupted redox homeostasis and elevated ROS levels are linked to various diseases, including cancer and neurodegenerative disorders. MutT homolog 1 (MTH1) is a critical enzyme that protects against oxidative DNA damage by eliminating oxidized dNTPs. This study explored MTH1 as a drug target, screened 18,000 natural compounds from the IMMPAT library using structure-based drug design approaches. The most suitable candidates were identified through a rigorous process that included physicochemical and pharmacokinetic profiling, pan-assay interference compounds, and prediction of activity spectra for substances analysis (PASS). This screening process, designed to ensure the selection of most promising compounds, that were Vinburnine and Norstephalagine. These molecules demonstrated high binding affinity for MTH1 and exhibited favorable pharmacokinetic properties based on ADMET and PASS analyses. Detailed interaction analysis revealed that both Vinburnine and Norstephalagine effectively occupy the binding pocket of MTH1, engaging with its active site residues. Further molecular dynamics simulations confirmed the stability of the MTH1-Vinburnine and MTH1-Norstephalagine complexes, showing minimal structural deviations from the native MTH1 enzyme. This study also employed BAY-707 as a positive control and CID:11150163 as a negative control to validate the binding affinities and interaction profiles of the identified hits. In conclusion, our study identified Vinburnine and Norstephalagine as potent MTH1 inhibitors with significant potential for therapeutic development against cancer and other diseases associated with MTH1 dysfunction. These findings highlight these compounds as promising therapeutic candidates and provide a foundation for the rational design of future MTH1 inhibitors for the therapeutic targeting of cancer and neurodegenerative diseases.