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A homology model for Clostridium difficile methionyl tRNA synthetase: active site analysis and docking interactions

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Abstract

Treatment of C. difficile infection is one of the most difficult biomedical challenges. To develop novel antibacterials, researchers have been targeting bacterial molecular functions that are essential for its growth. The methionyl tRNA synthetase (MetRS) is strictly required for protein biosynthesis and success was reported in developing antibacterials to inhibit this enzyme. The present study was aimed at building and analyzing a homology model for C. difficile MetRS in the context of drug design. A homology model of C. difficile MetRS was constructed using Molecular Operating Environment (MOE) software. A. aeolicus MetRS was the main template while the query zinc binding domain was modeled using T. thermophilus MetRS. The model has been assessed and compared to its main template (Ramachandran, ERRAT and ProSA). The active site of the query protein has been predicted from its sequence using a detailed conservation analysis (ClustalW2). Using MOE software, suitable ligands were docked in the constructed model, including a C. difficile MetRS inhibitor REP3123 and the enzyme natural substrate, and the key active site residues and interactions were identified. These docking studies have validated the active site conformation in the constructed model and identified binding interactions.

Final C. difficile Met-tRNA homology model and docking interaction of the inhibitor REP3123

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Authors and Affiliations

  1. Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK

    Ehab Al-Moubarak & Claire Simons

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  1. Ehab Al-Moubarak
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  2. Claire Simons
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Correspondence to Claire Simons.

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Al-Moubarak, E., Simons, C. A homology model for Clostridium difficile methionyl tRNA synthetase: active site analysis and docking interactions. J Mol Model 17, 1679–1693 (2011). https://doi.org/10.1007/s00894-010-0871-9

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  • DOI: https://doi.org/10.1007/s00894-010-0871-9

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