4LP0

Crystal structure of a topoisomerase ATP inhibitor

Summary for 4LP0

• Entry DOI: 10.2210/pdb4lp0/pdb
• Related: 4LPB
• Descriptor: Topoisomerase IV subunit B, 6'-[(ethylcarbamoyl)amino]-4'-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-3,3'-bipyridine-5-carboxylic acid (3 entities in total)
• Functional Keywords: protein-inhibitor complex, atp binding, structure-based drug design, antimicrobial, virtual screen, atpase domain, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 25038.12

Authors

Basarab, G.S.,Manchester, J.I.,Bist, S.,Boriack-Sjodin, P.A.,Dangel, B.,Illingsworth, R.,Uria-Nickelsen, M.,Sherer, B.A.,Sriram, S.,Eakin, A.E. (deposition date: 2013-07-14, release date: 2013-11-13, Last modification date: 2024-02-28)

Primary citation

Basarab, G.S.,Manchester, J.I.,Bist, S.,Boriack-Sjodin, P.A.,Dangel, B.,Illingworth, R.,Sherer, B.A.,Sriram, S.,Uria-Nickelsen, M.,Eakin, A.E.
Fragment-to-Hit-to-Lead Discovery of a Novel Pyridylurea Scaffold of ATP Competitive Dual Targeting Type II Topoisomerase Inhibiting Antibacterial Agents.
J.Med.Chem., 56:8712-8735, 2013

PubMed Abstract: The discovery and optimization of a new class of bacterial topoisomerase (DNA gyrase and topoisomerase IV) inhibitors binding in the ATP domain are described. A fragment molecule, 1-ethyl-3-(2-pyridyl)urea, provided sufficiently potent enzyme inhibition (32 μM) to prompt further analogue work. Acids and acid isosteres were incorporated at the 5-pyridyl position of this fragment, bridging to a key asparagine residue, improving enzyme inhibition, and leading to measurable antibacterial activity. A CF3-thiazole substituent at the 4-pyridyl position improved inhibitory potency due to a favorable lipophilic interaction. Promising antibacterial activity was seen versus the Gram-positive pathogens Staphylococcus aureus and Streptococcus pneumoniae and the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis . Precursor metabolite incorporation and mutant analysis studies support the mode-of-action, blockage of DNA synthesis by dual target topoisomerase inhibition. Compound 35 was efficacious in a mouse S. aureus disease model, where a 4.5-log reduction in colony forming units versus control was demonstrated.

PubMed: 24098982
DOI: 10.1021/jm401208b

Experimental method

X-RAY DIFFRACTION (1.95 Å)