6chp

Phosphopantetheine adenylyltransferase (CoaD) in complex with methyl (R)-4-(3-(2-cyano-1-((5-methyl-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)benzyl)piperidine-1-carboxylatePhosphopantetheine adenylyltransferase (CoaD) in complex with methyl (R)-4-(3-(2-cyano-1-((5-methyl-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)benzyl)piperidine-1-carboxylate

Structural highlights

6chp is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Activity:	Pantetheine-phosphate adenylyltransferase, with EC number 2.7.7.3
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[COAD_ECOLI] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate.

Publication Abstract from PubMed

In the preceding manuscript 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.

Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity.,Skepper CK, Moreau RJ, Appleton BA, Benton BM, Drumm JE, Feng BY, Geng M, Lingel A, Lu Y, Mamo M, Mergo W, Mostafavi M, Rath CM, Steffek M, Takeoka KT, Uehara K, Wang L, Wei JR, Xie L, Xu W, Zhang Q, Li C, de Vicente J J Med Chem. 2018 Mar 18. doi: 10.1021/acs.jmedchem.7b01861. PMID:29551072^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Skepper CK, Moreau RJ, Appleton BA, Benton BM, Drumm JE, Feng BY, Geng M, Lingel A, Lu Y, Mamo M, Mergo W, Mostafavi M, Rath CM, Steffek M, Takeoka KT, Uehara K, Wang L, Wei JR, Xie L, Xu W, Zhang Q, Li C, de Vicente J. Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity. J Med Chem. 2018 Mar 18. doi: 10.1021/acs.jmedchem.7b01861. PMID:29551072 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01861

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OCA

[1] Skepper CK, Moreau RJ, Appleton BA, Benton BM, Drumm JE, Feng BY, Geng M, Lingel A, Lu Y, Mamo M, Mergo W, Mostafavi M, Rath CM, Steffek M, Takeoka KT, Uehara K, Wang L, Wei JR, Xie L, Xu W, Zhang Q, Li C, de Vicente J. Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity. J Med Chem. 2018 Mar 18. doi: 10.1021/acs.jmedchem.7b01861. PMID:29551072 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01861

[1]

6chp

Structural highlights

Function

Publication Abstract from PubMed

References

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6chp

Structural highlights

Function

Publication Abstract from PubMed

References

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