Levente M. Mihalovits, György G. Ferenczy, and György M. Keserű
Journal of Chemical Information and Modeling 2019 59 (12), 5161-5173DOI: 10.1021/acs.jcim.9b00691
UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) catalyzes the first step in the biosynthesis of the bacterial cell wall. This pathway is essential for the growth of bacteria but missing in mammals, that nominates MurA as an attractive antibacterial target. MurA has a flexible loop whose conformational change is known to be part of the activation mechanism of the enzyme. We have shown that the loop closed conformation makes the proton transfer from Cys115 to His394 possible by a low barrier exothermic process. QM/MM MD simulations revealed that the activated thiolate is able to react with phosphoenolpyruvate (PEP), the natural substrate of MurA. The binding free energy profile of several covalent inhibitors with various warheads reacting with the activated Cys115 was calculated by QM/MM MD simulations and confirmed that reaction barrier heights tend to separate active from inactive compounds. Our results give new insight into the catalytic mechanism and covalent inhibition of MurA and suggest that QM/MM MD simulations are able to support ligand design by providing sensible relative free energy barriers for covalent inhibitors with various warheads reacting with thiolate nucleophiles.