Crystallographic study of inhibitors of tRNA-guanine transglycosylase suggests a new structure-based pharmacophore for virtual screening |
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Authors: | Brenk Ruth Meyer Emmanuel A Reuter Klaus Stubbs Milton T Garcia George A Diederich François Klebe Gerhard |
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Institution: | Institut für Pharmazeutische Chemie, Philipps-Universit?t Marburg, Marbacher Weg 6, 35032 Marburg, Germany. |
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Abstract: | The enzyme tRNA-guanine transglycosylase (TGT) is involved in the pathogenicity of Shigellae. As the crystal structure of this protein is known, it is a putative target for the structure-based design of inhibitors. Here we report a crystallographic study of several new ligands exhibiting a 2,6-diamino-3H-quinazolin-4-one scaffold, which has been shown recently to be a promising template for TGT-inhibitors. Crystal structure analysis of these complexes has revealed an unexpected movement of the side-chain of Asp102. A detailed analysis of the water network disrupted by this rotation has lead to the derivation of a new composite pharmacophore. A virtual screening has been performed based on this pharmacophore hypothesis and several new inhibitors of micromolar binding affinity with new skeletons have been discovered. |
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Keywords: | TGT crystallography inhibitors ligands |
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