Binding free energy calculations of N-sulphonyl-glutamic acid inhibitors of MurD ligase

Abstract

The increasing incidence of bacterial resistance to most available antibiotics has underlined the urgent need for the discovery of novel efficacious antibacterial agents. The biosynthesis of bacterial peptidoglycan, where the MurD enzyme is involved in the intracellular phase of UDP-MurNAc-pentapeptide formation, represents a collection of highly selective targets for novel antibacterial drug design. Structural studies of N-sulfonyl-glutamic acid inhibitors of MurD have made possible the examination of binding modes of this class of compounds, providing valuable information for the lead optimization phase of the drug discovery cycle. Binding free energies were calculated for a series of MurD N-sulphonyl-Glu inhibitors using the linear interaction energy (LIE) method. Analysis of interaction energy during the 20-ns MD trajectories revealed non-polar van der Waals interactions as the main driving force for the binding of these inhibitors, and excellent agreement with the experimental free energies was obtained. Calculations of binding free energies for selected moieties of compounds in this structural class substantiated even deeper insight into the source of inhibitory activity. These results constitute new valuable information to further assist the lead optimization process.

MurD enzymes: some recent developments

“…The outcome was a series of new inhibitors with the most potent compound (24), which inhibits MurD with an IC 50 value of 85 μmol/l. The binding energies of the naphthalene sulfonamides were calculated using the linear interaction energy method; the calculated energies correlated very well with the experimentally obtained free energies (96). Further analysis of the interactions between naphthalene sulfonamides and MurD was performed by nuclear magnetic resonance followed by molecular dynamics, which takes into account the ligand flexibility and its effect on particular ligand-enzyme contact, thus offering potential explanations for moderate inhibitory activities (97).…”

A challenging system: Free energy prediction for factor Xa

“…This is in accord- ance with earlier studies on MurD ligase. 69 Electrostatics turned out to be of importance to orient the ligands; however, differences in binding energies were also found to be mainly caused by van der Waals interactions.…”

Binding Modes of Three Inhibitors 8CA, F8A and I4A to A-FABP Studied Based on Molecular Dynamics Simulation

“…The parameters , , and are Amber van der Waals radii linear scaling coefficient, the solute interior dielectric constant, the molecular surface area coefficient and a constant, respectively. The parameter corresponds to the global proportionality coefficient related to the loss of conformational entropy upon binding [54]. The optimized values of these parameters are , , , kcal/(mol·Å 2 ) and kcal·mol −1 , respectively [48], [50].…”