Molecular dynamics simulations of s-triazine-based MMP-10 inhibitor with ferroptosis induction capacity and potent anti-colorectal cancer activities

The present study explores the dynamic behavior and binding stability of a novel s-triazine-based MMP-10 inhibitor with ferroptosis induction capacity through comprehensive molecular dynamics (MD) simulations. The investigated compound, referred to as compound (I), demonstrated potent anti-colorectal cancer activities (HCT-116; IC50 = 0.018 μM). Mechanistically, the title compound (I) surpassed the reference MMPs inhibitor NNGH against MMP-10 (IC50 = 0.16 μM), depleted GSH in HCT-116 cells (relative fold decrement = 0.81) with modest GPX4 inhibition, and induced lipid peroxidation by 1.32 relative fold increment. Employing GROMACS program MD simulations were conducted for 100 ns to assess the complex's root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), ligand interaction network, contact frequency analysis, and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) binding free energy calculations aiming to elucidate the molecular tenets responsible for its anti-colorectal cancer activities. The results show that compound (I) has a stable and consistent interaction within the MMP-10 active site, which supports its promising inhibitory effect and prospective therapeutic application in colorectal cancer treatment. Colorectal cancer (CRC) is the third most frequent malignancy and the fourth most prevalent cause of cancer-related mortality.