Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design
| Autor: | Yuanhong Li, Cynthia Hess Kenny, Desiree H.H. Tsao, A. Karl Malakian, Russell Dushin, Ramaswamy Nilakantan, Weidong Ding, Elizabeth G. Dushin, Alan G. Sutherland, Lidia Mosyak, Lee D. Jennings, Thomas S. Rush, Juan C. Alvarez, Steve A. Haney |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry Clinical Biochemistry Fragment-based lead discovery Drug Evaluation Preclinical Pharmaceutical Science Cell Cycle Proteins Plasma protein binding Crystallography X-Ray Ligands Biochemistry Structure-Activity Relationship Drug Discovery Structure–activity relationship FtsZ Molecular Biology Antibacterial agent biology Chemistry Escherichia coli Proteins Organic Chemistry Nuclear magnetic resonance spectroscopy Small molecule Peptide Fragments Anti-Bacterial Agents Drug Design Multiprotein Complexes biology.protein Molecular Medicine Carrier Proteins Hydrophobic and Hydrophilic Interactions Heteronuclear single quantum coherence spectroscopy Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry. 14(23) |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect