4MBC

Structure of Streptococcus pneumonia ParE in complex with AZ13053807

Summary for 4MBC

• Entry DOI: 10.2210/pdb4mbc/pdb
• Related: 4EM7 4EMV 4MB9
• Descriptor: DNA topoisomerase IV, B subunit, 1-{5-[2-(morpholin-4-yl)ethoxy]-6-(pyridin-3-yl)[1,3]thiazolo[5,4-b]pyridin-2-yl}-3-prop-2-en-1-ylurea (3 entities in total)
• Functional Keywords: atp binding, structure-based drug design, antimicrobial, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 25041.24

Authors

Ogg, D.,Tucker, J. (deposition date: 2013-08-19, release date: 2013-10-16, Last modification date: 2024-02-28)

Primary citation

Kale, M.G.,Raichurkar, A.,Hameed, S.P.,Waterson, D.,McKinney, D.,Manjunatha, M.R.,Kranthi, U.,Koushik, K.,Jena, L.K.,Shinde, V.,Rudrapatna, S.,Barde, S.,Humnabadkar, V.,Madhavapeddi, P.,Basavarajappa, H.,Ghosh, A.,Ramya, V.,Guptha, S.,Sharma, S.,Vachaspati, P.,Kumar, K.N.,Giridhar, J.,Reddy, J.,Panduga, V.,Ganguly, S.,Ahuja, V.,Gaonkar, S.,Kumar, C.N.,Ogg, D.,Tucker, J.A.,Boriack-Sjodin, P.A.,de Sousa, S.M.,Sambandamurthy, V.K.,Ghorpade, S.R.
Thiazolopyridine Ureas as Novel Antitubercular Agents Acting through Inhibition of DNA Gyrase B.
J.Med.Chem., 56:8834-8848, 2013

PubMed Abstract: A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 μM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.

PubMed: 24088190
DOI: 10.1021/jm401268f

Experimental method

X-RAY DIFFRACTION (1.75 Å)