In silico and in vitro Identification of Compounds with Dual Pharmacological Activity against Metionyl‐tRNA Synthetase and Isoleucyl‐tRNA Synthetase of Staphylococcus aureus

Abstract

AbstractThe spread of drug‐resistant Staphylococcus aureus (S. aureus) in hospitals and communities poses a serious medical threat. This study aimed to identify aminoacyl‐tRNA synthetase inhibitors with antimicrobial activity against S. aureus. In silico structure‐based drug screening using docking and molecular dynamics simulations (MDS) was performed targeting S. aureus metionyl‐tRNA synthetase (saMetRS). Ten candidate compounds were selected by screening a compound 3D structure library with 154,118 compounds. One compound (Compound 9) showed a strong inhibitory effect in growth inhibition studies using Staphylococcus epidermidis. From the experiments verifying the dose‐dependent effect, the IC50 value of Compound 9 was determined to be 3.74 μM. MDSs predicted that Compound 9 exhibits inhibitory activity against saMetRS and S. aureus isoleucyl‐tRNA synthetase, which belongs to the same subclass Ia. Compound 9 with its polypharmacological activity is not susceptible to drug resistance and is expected to have enhanced antimicrobial efficacy.