6OW2

X-ray Structure of Polypeptide Deformylase

Summary for 6OW2

• Entry DOI: 10.2210/pdb6ow2/pdb
• Descriptor: Peptide deformylase, NICKEL (II) ION, (2R)-2-(cyclopentylmethyl)-N'-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methylpyrimidin-4-yl}-3-[hydroxy(hydroxymethyl)amino]propanehydrazide, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, metal protein, enzyme, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 23130.11

Authors

Campobasso, N.,Spletstoser, J.,Ward, P. (deposition date: 2019-05-09, release date: 2019-06-26, Last modification date: 2024-03-13)

Primary citation

Spletstoser, J.T.,Dreabit, J.,Knox, A.N.,Benowitz, A.,Campobasso, N.,Ward, P.,Cui, G.,Lewandowski, T.,McCloskey, L.,Aubart, K.M.
Discovery of piperazic acid peptide deformylase inhibitors with in vivo activity for respiratory tract and skin infections.
Bioorg.Med.Chem.Lett., 29:2410-2414, 2019

PubMed Abstract: The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds. We describe lead optimization of the P3' region of the series that resulted in a compound with good potency against three target organisms. One molecule showed in vivo efficacy in a rat respiratory infection model but ultimately did not meet candidate progression criteria.

PubMed: 31160176
DOI: 10.1016/j.bmcl.2019.05.028

Experimental method

X-RAY DIFFRACTION (1.7 Å)