4MOT

Structure of Streptococcus pneumonia pare in complex with AZ13072886

Summary for 4MOT

• Entry DOI: 10.2210/pdb4mot/pdb
• Related: 4EM7 4EMV 4MB9 4MBC
• Descriptor: Topoisomerase IV subunit B, 1-[4-(3-methylbutyl)-5-oxo-6-(pyridin-3-yl)-4,5-dihydro[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, virtual screen, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 24998.22

Authors

Ogg, D.,Boriack-Sjodin, P.A. (deposition date: 2013-09-12, release date: 2013-11-20, Last modification date: 2024-02-28)

Primary citation

Kale, R.R.,Kale, M.G.,Waterson, D.,Raichurkar, A.,Hameed, S.P.,Manjunatha, M.R.,Kishore Reddy, B.K.,Malolanarasimhan, K.,Shinde, V.,Koushik, K.,Jena, L.K.,Menasinakai, S.,Humnabadkar, V.,Madhavapeddi, P.,Basavarajappa, H.,Sharma, S.,Nandishaiah, R.,Mahesh Kumar, K.N.,Ganguly, S.,Ahuja, V.,Gaonkar, S.,Naveen Kumar, C.N.,Ogg, D.,Boriack-Sjodin, P.A.,Sambandamurthy, V.K.,de Sousa, S.M.,Ghorpade, S.R.
Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy.
Bioorg.Med.Chem.Lett., 24:870-879, 2014

PubMed Abstract: Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 μM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.

PubMed: 24405701
DOI: 10.1016/j.bmcl.2013.12.080

Experimental method

X-RAY DIFFRACTION (1.75 Å)