6CHM

Phosphopantetheine adenylyltransferase (CoaD) in complex with N-(2-(5-methoxy-1H-indol-3-yl)ethyl)pivalamide

Summary for 6CHM

• Entry DOI: 10.2210/pdb6chm/pdb
• Descriptor: Phosphopantetheine adenylyltransferase, N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-2,2-dimethylpropanamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: dephospho-coa pyrophosphorylase, pantetheine-phosphate adenylyltransferase, ppat caad, fbdd gram-negative antibacterial antibiotic, transferase transferase-antibiotic complex, transferase-antibiotic complex, transferase/antibiotic
• Biological source: Escherichia coli (strain K12)
• Cellular location: Cytoplasm : P0A6I6
• Total number of polymer chains: 2
• Total formula weight: 37176.72

Authors

Mamo, M.,Appleton, B.A. (deposition date: 2018-02-22, release date: 2018-04-04, Last modification date: 2024-03-13)

Primary citation

Skepper, C.K.,Moreau, R.J.,Appleton, B.A.,Benton, B.M.,Drumm, J.E.,Feng, B.Y.,Geng, M.,Hu, C.,Li, C.,Lingel, A.,Lu, Y.,Mamo, M.,Mergo, W.,Mostafavi, M.,Rath, C.M.,Steffek, M.,Takeoka, K.T.,Uehara, K.,Wang, L.,Wei, J.R.,Xie, L.,Xu, W.,Zhang, Q.,de Vicente, J.
Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity.
J. Med. Chem., 61:3325-3349, 2018

PubMed Abstract: In the preceding manuscript [ Moreau et al. 2018 , 10.1021/acs.jmedchem.7b01691 ] we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.

PubMed: 29551072
DOI: 10.1021/acs.jmedchem.7b01861

Experimental method

X-RAY DIFFRACTION (2.28 Å)