Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design.
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.
Tsao
Désirée H H
DH
Structural Biology and Computational Chemistry, Wyeth Research, Cambridge, MA 02140, USA. dtsao@wyeth.com
Sutherland
Alan G
AG
Jennings
Lee D
LD
Li
Yuanhong
Y
Rush
Thomas S
TS
Alvarez
Juan C
JC
Ding
Weidong
W
Dushin
Elizabeth G
EG
Dushin
Russell G
RG
Haney
Steve A
SA
Kenny
Cynthia H
CH
Malakian
A Karl
AK
Nilakantan
Ramaswamy
R
Mosyak
Lidia
L
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
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