3JZF

Crystal structure of biotin carboxylase from E. Coli in complex with benzimidazoles series

Summary for 3JZF

• Entry DOI: 10.2210/pdb3jzf/pdb
• Related: 3JZI
• Descriptor: Biotin carboxylase, CARBONATE ION, 2-[(2-chlorobenzyl)amino]-1-(cyclohexylmethyl)-1H-benzimidazole-5-carboxamide, ... (4 entities in total)
• Functional Keywords: biotin carboxylase, accc, acetyl coenzyme-a carboxylase, accase, atp-binding, biotin, fatty acid biosynthesis, ligase, lipid synthesis, nucleotide-binding
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 107471.04

Authors

Orth, P. (deposition date: 2009-09-23, release date: 2009-11-03, Last modification date: 2023-09-06)

Primary citation

Cheng, C.C.,Shipps, G.W.,Yang, Z.,Sun, B.,Kawahata, N.,Soucy, K.A.,Soriano, A.,Orth, P.,Xiao, L.,Mann, P.,Black, T.
Discovery and optimization of antibacterial AccC inhibitors.
Bioorg.Med.Chem.Lett., 19:6507-6514, 2009

PubMed Abstract: The biotin carboxylase (AccC) is part of the multi-component bacterial acetyl coenzyme-A carboxylase (ACCase) and is essential for pathogen survival. We describe herein the affinity optimization of an initial hit to give 2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzo[d]imidazole-5-carboxamide (1), which was identified using our proprietary Automated Ligand Identification System (ALIS).(1) The X-ray co-crystal structure of 1 was solved and revealed several key interactions and opportunities for further optimization in the ATP site of AccC. Structure Based Drug Design (SBDD) and parallel synthetic approaches resulted in a novel series of AccC inhibitors, exemplified by (R)-2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo[4,5-b]pyridine-5-carboxamide (40). This compound is a potent and selective inhibitor of bacterial AccC with an IC(50) of 20 nM and a MIC of 0.8 microg/mL against a sensitized strain of Escherichia coli (HS294 E. coli).

PubMed: 19875284
DOI: 10.1016/j.bmcl.2009.10.057

Experimental method

X-RAY DIFFRACTION (2.13 Å)