title: Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design.
abstract: ZipA is a membrane anchored protein in Escherichia coli that interacts with FtsZ, a homolog of eukaryotic tubulins, forming a septal ring structure that mediates bacterial cell division. Thus, the ZipA/FtsZ protein-protein interaction is a potential target for an antibacterial agent. We report here an NMR-based fragment screening approach which identified several hits that bind to the C-terminal region of ZipA. The screen was performed by 1H-15N HSQC experiments on a library of 825 fragments that are small, lead-like, and highly soluble. Seven hits were identified, and the binding mode of the best one was revealed in the X-ray crystal structure. Similar to the ZipA/FtsZ contacts, the driving force in the binding of the small molecule ligands to ZipA is achieved through hydrophobic interactions. Analogs of this hit were also evaluated by NMR and X-ray crystal structures of these analogs with ZipA were obtained, providing structural information to help guide the medicinal chemistry efforts.
authors.affiliation: Structural Biology and Computational Chemistry, Wyeth Research, Cambridge, MA 02140, USA. dtsao@wyeth.com
authors.forename: Désirée H H
authors.initials: DH
authors.lastname: Tsao
authors.forename: Alan G
authors.initials: AG
authors.lastname: Sutherland
authors.forename: Lee D
authors.initials: LD
authors.lastname: Jennings
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Li
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Rush
authors.forename: Juan C
authors.initials: JC
authors.lastname: Alvarez
authors.forename: Weidong
authors.initials: W
authors.lastname: Ding
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Dushin
authors.forename: Russell G
authors.initials: RG
authors.lastname: Dushin
authors.forename: Steve A
authors.initials: SA
authors.lastname: Haney
authors.forename: Cynthia H
authors.initials: CH
authors.lastname: Kenny
authors.forename: A Karl
authors.initials: AK
authors.lastname: Malakian
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Nilakantan
authors.forename: Lidia
authors.initials: L
authors.lastname: Mosyak
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D029968:Escherichia coli Proteins; C076835:FtsZ84 protein, E coli; D008024:Ligands; D046912:Multiprotein Complexes; D010446:Peptide Fragments; C103795:ZipA protein, E coli