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Mimicking direct protein–protein and solvent-mediated interactions in the CDP-methylerythritol kinase homodimer: a pharmacophore-directed virtual screening approach

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Abstract

The 2C-methylerythritol 4-phosphate (MEP) pathway for the biosynthesis of isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate, which are the precursors of isoprenoids, is present in plants, in the malaria parasite Plasmodium falciparum and in most eubacteria, including pathogenic agents. However, the MEP pathway is absent from fungi and animals, which have exclusively the mevalonic acid pathway. Given the characteristics of the MEP pathway, its enzymes represent potential targets for the generation of selective antibacterial, antimalarial and herbicidal molecules. We have focussed on the enzyme 4-(cytidine 5′-diphospho)-2-C-methyl-d-erythritol kinase (CMK), which catalyses the fourth reaction step of the MEP pathway. A molecular dynamics simulation was carried out on the CMK dimer complex, and protein–protein interactions analysed, considering also water-mediated interactions between monomers. In order to find small molecules that bind to CMK and disrupt dimer formation, interactions observed in the dynamics trajectory were used to model a pharmacophore used in database searches. Using an intensity-fading matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry approach, one compound was found to interact with CMK. The data presented here indicate that a virtual screening approach can be used to identify candidate molecules that disrupt the CMK–CMK complex. This strategy can contribute to speeding up the discovery of new antimalarial, antibacterial, and herbicidal compounds.

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Acknowledgements

The excellent technical assistance of Drs. Eliandre de Oliveira and Maria Antonia Odena Caballol, from the Proteomics Platform, Barcelona Science Park, in the intensity-fading MALDI-TOF mass spectrometry experiments is gratefully acknowledged. This work was financed in part with grants from the University of Barcelona (ACES-UB), the Spanish Ministerio de Ciencia y Tecnología (CTQ2006-06588/BQU, BIO2002-04419-C02-02 and BIO2008-01184) and the Generalitat de Catalunya (2005SGR00914).

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Author notes

  1. Óscar Villacañas

    Present address: Intelligent Pharma, S.L. Barcelona Science Park, Baldiri Reixac 10–12, 08028, Barcelona, Spain

Authors and Affiliations

  1. Department de Bioquímica i Biología Molecular, Universitat de Barcelona, Avda Diagonal 645, 08028, Barcelona, Spain

    Victor Giménez-Oya & Santiago Imperial

  2. Department de Química Física, Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain

    Óscar Villacañas & Jaime Rubio-Martinez

  3. Biomolecular Interactions Team, Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona Science Park, Baldiri Reixac 10–12, 08028, Barcelona, Spain

    Xavier Fernàndez-Busquets

  4. Nanoscience and Nanotechnology Institute, Universitat de Barcelona, Barcelona, Spain

    Xavier Fernàndez-Busquets & Santiago Imperial

Authors
  1. Victor Giménez-Oya
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  2. Óscar Villacañas
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  3. Xavier Fernàndez-Busquets
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  5. Santiago Imperial
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Corresponding author

Correspondence to Santiago Imperial.

Additional information

V. Giménez-Oya and Ó. Villacañas contributed equally to this work.

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Giménez-Oya, V., Villacañas, Ó., Fernàndez-Busquets, X. et al. Mimicking direct protein–protein and solvent-mediated interactions in the CDP-methylerythritol kinase homodimer: a pharmacophore-directed virtual screening approach. J Mol Model 15, 997–1007 (2009). https://doi.org/10.1007/s00894-009-0458-5

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  • DOI: https://doi.org/10.1007/s00894-009-0458-5

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