Journal of Molecular Modeling

, Volume 15, Issue 8, pp 983–996

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


  • Andrej Perdih
    • Laboratory for Molecular Modeling and NMR SpectroscopyNational Institute of Chemistry
  • Urban Bren
    • Laboratory for Molecular Modeling and NMR SpectroscopyNational Institute of Chemistry
    • Laboratory for Molecular Modeling and NMR SpectroscopyNational Institute of Chemistry
Original Paper

DOI: 10.1007/s00894-009-0455-8

Cite this article as:
Perdih, A., Bren, U. & Solmajer, T. J Mol Model (2009) 15: 983. doi:10.1007/s00894-009-0455-8


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.


Antibacterial agentsDrug designLinear interaction energy (LIE) methodMolecular dynamics (MD) simulationsMurD ligaseN-sulfonyl-glutamic acid derivatives

Supplementary material

894_2009_455_MOESM1_ESM.pdf (7 mb)
Supplementary Material(a) Tables of partial atomic charges and atom types of N-sulfonyl-D-glutamic acid derivatives 1–12 and side chain of carbamylated Lys198 (KCX moiety). (b) The time dependence of all distances monitored along the 20 ns MD trajectories. (c) RMSD plots of conformations of inhibitors 1 and 2 produced during the MD simulations with respect to their conformations in the crystal structures. (d) Interaction energy between compound 3 and its surrounding (water and sodium ions in the free state (blue) and water, sodium ions and protein in the bound state (red)) during the 20 ns MD simulation. (e) Two animations presenting bound and free state of compound 4 during the MD simulation (PDF 6.96 MB)
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Bound_state (MPG 6.96 MB)

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Free_state (MPG 6.96 MB)

Copyright information

© Springer-Verlag 2009