Structure based prediction of selective MraY inhibitors

Antibiotic resistance is becoming a growing concern of public health and hence there is an increasing demand for developing better antibiotic strategies. One such strategy includes targeting the bacterial cell wall, thereby killing the bacteria. A bacterial transmembrane enzyme MraY (Phospho-N-acetylmuramoyl-pentapeptide translocase), is considered to be a promising target for developing new antibiotics since it is involved in cell wall synthesis. Tunicamycin is an antibiotic known to inhibit the function of MraY. However, it shows cross-reactivity with the structurally homologous human enzyme hGPT (GlcNAc-1-P-transferase), which therefore calls for antibiotics with MraY selectivity. In the present computational work, we identified selective MraY inhibitors, where virtual screening of 45,411 compounds was carried out, followed by molecular dynamics simulations to check the stability of key inhibitory interactions across MraY and hGPT. From five shortlisted tentative inhibitors, comparative structural interaction analysis for both MraY and hGPT suggested three compounds as potential selective MraY inhibitors.