caa a22 4500 467939047 CHVBK 20180406153006.0 cr unu---uuuuu 170328e20061001xx s 000 0 eng 10.1007/s10822-006-9062-2 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9062-2 Molecular modeling and bioinformatical analysis of the antibacterial target enzyme MurA from a drug design perspective [Elektronische Daten] [Christian Klein, 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. Springer Science+Business Media B.V., 2006 Antibiotics nationallicence Drug design nationallicence Enzyme inhibition nationallicence Molecular dynamics simulation nationallicence Multiple sequence alignment nationallicence MurA nationallicence EC 2.5.1.7 nationallicence Klein Christian Pharmazeutische und Medizinische Chemie, Saarland University FR 8.2, Am Stadtwald, P.O. Box 15 11 50, D-66041, Saarbrücken, Germany aut Bachelier Anke Pharmazeutische und Medizinische Chemie, Saarland University FR 8.2, Am Stadtwald, P.O. Box 15 11 50, D-66041, Saarbrücken, Germany aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/10-11(2006-10-01), 621-628 0920-654X 20:10-11<621 2006 20 10822 https://doi.org/10.1007/s10822-006-9062-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9062-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Klein Christian Pharmazeutische und Medizinische Chemie, Saarland University FR 8.2, Am Stadtwald, P.O. Box 15 11 50, D-66041, Saarbrücken, Germany aut NATIONALLICENCE 700 1- Bachelier Anke Pharmazeutische und Medizinische Chemie, Saarland University FR 8.2, Am Stadtwald, P.O. Box 15 11 50, D-66041, Saarbrücken, Germany aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/10-11(2006-10-01), 621-628 0920-654X 20:10-11<621 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer