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Molecular dynamics simulation and linear interaction energy study of d-Glu-based inhibitors of the MurD ligase

Abstract

The biosynthetic pathway of the bacterial peptidoglycan, where MurD is an enzyme involved at the intracellular stage of its construction, represents a collection of highly selective macromolecular targets for novel antibacterial drug design. In this study as part of our investigation of the MurD bacterial target two recently discovered classes of the MurD ligase inhibitors were investigated resulting from the lead optimization phases of the N-sulfonamide d-Glu MurD inhibitors. Molecular dynamics simulations, based on novel structural data, in conjunction with the linear interaction energy (LIE) method suggested the transferability of our previously obtained LIE coefficients to further d-Glu based classes of MurD inhibitors. Analysis of the observed dynamical behavior of these compounds in the MurD active site was supported by static drug design techniques. These results complement the current knowledge of the MurD inhibitory mechanism and provide valuable support for the d-Glu paradigm of the inhibitor design.

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Acknowledgments

This work was supported by the postdoctoral grant of the Ministry of Higher Education, Science and Technology of the Republic of Slovenia (Grant Number: Z1-4111).The authors would like thank Dr. Jernej Zidar and Barbara Pogorelčnik from the National institute of Chemistry, Slovenia, for their helpful technical assistance and Dr. Yasmin Aristei from Molecular Discovery Ltd. for GRID map calculations. Dr. Urban Bren from the National Institute of Chemistry, Ljubljana is acknowledged for introducing us to LIE methodology in our previous binding study of MurD inhibitors.

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Correspondence to Andrej Perdih.

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Perdih, A., Wolber, G. & Solmajer, T. Molecular dynamics simulation and linear interaction energy study of d-Glu-based inhibitors of the MurD ligase. J Comput Aided Mol Des 27, 723–738 (2013). https://doi.org/10.1007/s10822-013-9673-3

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  • DOI: https://doi.org/10.1007/s10822-013-9673-3

Keywords

  • Molecular dynamics (MD) simulations
  • Linear interaction energy (LIE) method
  • Structure-based pharmacophore models
  • MurD ligase
  • Antibacterial agents
  • Drug design