4unq

Mtb TMK in complex with compound 36

spinqualitylabelsall models 4unq, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4unq is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: H6D, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KTHY_MYCTU Catalyzes the reversible phosphorylation of deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), using ATP as its preferred phosphoryl donor. Situated at the junction of both de novo and salvage pathways of deoxythymidine triphosphate (dTTP) synthesis, is essential for DNA synthesis and cellular growth. Has a broad specificity for nucleoside triphosphates, being highly active with ATP or dATP as phosphate donors, and less active with ITP, GTP, CTP and UTP.[HAMAP-Rule:MF_00165] Publication Abstract from PubMed M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and an NMR based fragment screen through which we discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively. We describe three cyanopyridone subseries that arose during our hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment hit from 500 muM to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivatives containing sulfoxides and sulfones showed cellular activity against M. tuberculosis. To the best of our knowledge, these compounds are the first reports of non-thymidine-like inhibitors of Mtb TMK. Structure guided lead generation for M. tuberculosis thymidylate kinase (Mtb TMK): discovery of 3-cyanopyridone and 1,6-naphthyridin-2-one as potent inhibitors.,Naik M, Raichurkar A, Bandodkar BS, Varun BV, Bhat S, Kalkhambkar R, Murugan K, Menon R, Bhat J, Paul B, Iyer H, Hussein S, Tucker JA, Vogtherr M, Embrey KJ, McMiken H, Prasad S, Gill A, Ugarkar BG, Venkatraman J, Read J, Panda M J Med Chem. 2015 Jan 22;58(2):753-66. doi: 10.1021/jm5012947. Epub 2014 Dec 23. PMID:25486447 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate kinase 3D structures

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