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  • Title: Discovery of new inhibitors of resistant Streptococcus pneumoniae penicillin binding protein (PBP) 2x by structure-based virtual screening.
    Author: Miguet L, Zervosen A, Gerards T, Pasha FA, Luxen A, Distèche-Nguyen M, Thomas A.
    Journal: J Med Chem; 2009 Oct 08; 52(19):5926-36. PubMed ID: 19746934.
    Abstract:
    Penicillin binding proteins (PBPs) are involved in the biosynthesis of the peptidoglycan layer constitutive of the bacterial envelope. They have been targeted for more than half a century by extensively derived molecular scaffolds of penicillins and cephalosporins. Streptococcus pneumoniae resists the antibiotic pressure by inducing highly mutated PBPs that can no longer bind the beta-lactam containing agents. To find inhibitors of PBP2x from Streptococcus pneumoniae (spPBP2x) with novel chemical scaffold so as to circumvent the resistance problems, a hierarchical virtual screening procedure was performed on the NCI database containing approximately 260000 compounds. The calculations involved ligand-based pharmacophore mapping studies and molecular docking simulations in a homology model of spPBP2x from the highly resistant strain 5204. A total of 160 hits were found, and 55 were available for experimental tests. Three compounds harboring two novel chemical scaffolds were identified as inhibitors of the resistant strain 5204-spPBP2x at the micromolar range.
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