6KZX

Crystal structure of E.coli DNA gyrase B in complex with 2-oxo-1,2-dihydroquinoline derivative

Summary for 6KZX

• Entry DOI: 10.2210/pdb6kzx/pdb
• Related: 6kzv
• Descriptor: DNA gyrase subunit B, 3-[[8-(methylamino)-2-oxidanylidene-1~{H}-quinolin-3-yl]carbonylamino]benzoic acid (3 entities in total)
• Functional Keywords: inhibitor, complex, topoisomerase, escherichia coli, isomerase
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 24528.51

Authors

Mima, M.,Takeuchi, T.,Ushiyama, F. (deposition date: 2019-09-25, release date: 2020-05-06, Last modification date: 2023-11-22)

Primary citation

Ushiyama, F.,Amada, H.,Takeuchi, T.,Tanaka-Yamamoto, N.,Kanazawa, H.,Nakano, K.,Mima, M.,Masuko, A.,Takata, I.,Hitaka, K.,Iwamoto, K.,Sugiyama, H.,Ohtake, N.
Lead Identification of 8-(Methylamino)-2-oxo-1,2-dihydroquinoline Derivatives as DNA Gyrase Inhibitors: Hit-to-Lead Generation Involving Thermodynamic Evaluation.
Acs Omega, 5:10145-10159, 2020

PubMed Abstract: DNA gyrase and topoisomerase IV are well-validated pharmacological targets, and quinolone antibacterial drugs are marketed as their representative inhibitors. However, in recent years, resistance to these existing drugs has become a problem, and new chemical classes of antibiotics that can combat resistant strains of bacteria are strongly needed. In this study, we applied our hit-to-lead (H2L) chemistry for the identification of a new chemical class of GyrB/ParE inhibitors by efficient use of thermodynamic parameters. Investigation of the core fragments obtained by fragmentation of high-throughput screening hit compounds and subsequent expansion of the hit fragment was performed using isothermal titration calorimetry (ITC). The 8-(methylamino)-2-oxo-1,2-dihydroquinoline derivative showed potent activity against DNA gyrase with an IC value of 0.0017 μM. In this study, we demonstrated the use of ITC for primary fragment screening, followed by structural optimization to obtain lead compounds, which advanced into further optimization for creating novel antibacterial agents.

PubMed: 32391502
DOI: 10.1021/acsomega.0c00865

Experimental method

X-RAY DIFFRACTION (2.1 Å)