Journal of Computer-Aided Molecular Design

, Volume 20, Issue 10–11, pp 621–628 | Cite as

Molecular modeling and bioinformatical analysis of the antibacterial target enzyme MurA from a drug design perspective

  • Christian D. KleinEmail author
  • Anke Bachelier


The enzyme MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) catalyzes the first cytoplasmatic step in the synthesis of murein precursors. This function is of vital relevance for bacteria, and the enzyme therefore represents an important target protein for the development of novel antibacterial compounds. Several X-ray structures of liganded and un-liganded MurA have been published, which may be used for rational drug design. MurA, however, contains a highly flexible surface loop, which is involved in substrate and inhibitor binding. In the available X-ray structures, the conformation of this surface loop varies, depending on the presence or absence of ligands or substrate and probably also on the crystal packing. The uncertainty of the low-energy, or “resting state” conformation of this surface loop hampers the application of rational drug design to this class of enzymes. We have therefore performed an extensive molecular dynamics study of the enzyme in order to identify one or several low-energy conformers. The results indicate that, at least in some of the X-ray structures, the conformation of the flexible surface loop is influenced by crystallographic contacts. Furthermore, three partially helical foldamers of the surface loop are identified which may resemble the resting states of the enzyme or intermediate states that are “traversed” during the substrate binding process. Another, very important aspect for the development of novel antibacterial compounds is the inter- and intra-species variability of the target structure. We present a comparison of MurA sequences from 163 organisms which were analyzed under the aspects of enzyme mechanism, structure and drug design. The results allow us to identify the most promising binding sites for inhibitor interaction, which are present in MurA enzymes of most species and are expected to be insusceptible to resistance-inducing mutations.


Antibiotics Drug design Enzyme inhibition Molecular dynamics simulation Multiple sequence alignment MurA EC 



UDP-N-acetylglucosamine enolpyruvyl transferase






root-mean-square deviation


molecular dynamics



The work has been performed under the Project HPC-EUROPA (RII3-CT-2003-506079), with the support of the European Community—Research Infrastructure Action under the FP6 “Structuring the European Research Area” Programme. This project was supported by the Deutsche Forschungsgemeinschaft (KL 1356) and the Fonds der Chemischen Industrie. We thank Professor R. Hartmann for his continued support of our work.


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Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.Pharmazeutische und Medizinische ChemieSaarland University FR 8.2SaarbrückenGermany

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