Discovery of new inhibitors of resistant Streptococcus pneumoniae penicillin binding protein (PBP) 2x by structure-based virtual screening.
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.
Miguet
Laurence
L
Laboratoire de Dynamique Moleculaire, Institut de Biologie Structurale Jean-Pierre Ebel (CEA/CNRS/UJF), Grenoble, France.
Zervosen
Astrid
A
Gerards
Thomas
T
Pasha
Farhan A
FA
Luxen
André
A
Distèche-Nguyen
Martine
M
Thomas
Aline
A
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
D008024:Ligands; D046915:Penicillin-Binding Proteins; C072223:PBP 2x protein, Streptococcus