title: Discovery of new inhibitors of resistant Streptococcus pneumoniae penicillin binding protein (PBP) 2x by structure-based virtual screening.
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.
authors.affiliation: Laboratoire de Dynamique Moleculaire, Institut de Biologie Structurale Jean-Pierre Ebel (CEA/CNRS/UJF), Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Miguet
authors.forename: Astrid
authors.initials: A
authors.lastname: Zervosen
authors.forename: Thomas
authors.initials: T
authors.lastname: Gerards
authors.forename: Farhan A
authors.initials: FA
authors.lastname: Pasha
authors.forename: André
authors.initials: A
authors.lastname: Luxen
authors.forename: Martine
authors.initials: M
authors.lastname: Distèche-Nguyen
authors.forename: Aline
authors.initials: A
authors.lastname: Thomas
mesh_terms: D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D024881:Drug Resistance, Bacterial; D008024:Ligands; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D046915:Penicillin-Binding Proteins; C072223:PBP 2x protein, Streptococcus