Molecular Insights Into the Role of the Gallate Moiety in Catechin Derivatives as Inhibitors of Wild‐Type and Mutant Dihydrofolate Reductases From Staphylococcus aureus

ABSTRACT Catechins are flavonoids characterized by aromatic rings and multiple hydroxyl groups. Green tea is one of the richest natural sources of these compounds and has been associated with several beneficial therapeutic effects. In this study, the inhibitory potential of the principal catechins found in green tea, along with ten catechin‐derived compounds, was investigated using molecular docking and molecular dynamics simulations to evaluate their potential as dihydrofolate reductase (DHFR) inhibitors. The studied compounds were evaluated against the inhibitory sites of DHFR_WT (wild‐type) and DHFR_S1 (mutant) from Staphylococcus aureus . The stability and dynamic behavior of the resulting complexes were analyzed through RMSD values, hydrogen‐bond residence times, free energy calculations, and intermolecular interaction analyses. These results allowed the identification of the most promising ligands and provided insights into the inhibition mechanism of the studied enzymes. The findings also indicate that the stability of the complexes is strongly influenced by the hydroxyl substituents on the gallate moiety, rather than by other positional variations in the catechin scaffold. This observation highlights the potential for the rational design of highly specific DHFR inhibitors.