4UNS

Mtb TMK in complex with compound 40

Summary for 4UNS

• Entry DOI: 10.2210/pdb4uns/pdb
• Related: 4UNN 4UNP 4UNQ 4UNR
• Descriptor: THYMIDYLATE KINASE, N-[4-(3-CYANO-7-ETHYL-5-METHYL-2-OXO-1H-1,6-NAPHTHYRIDIN-4-YL)PHENYL]METHANESULFONAMIDE, SODIUM ION, ... (4 entities in total)
• Functional Keywords: transferase, atp tmp phosphotransferase
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 2
• Total formula weight: 45339.08

Authors

Read, J.A.,Hussein, S.,Gingell, H.,Tucker, J. (deposition date: 2014-05-30, release date: 2015-06-17, Last modification date: 2024-01-10)

Primary citation

Naik, M.,Raichurkar, A.,Bandodkar, B.S.,Varun, B.V.,Bhat, S.,Kalkhambkar, R.,Murugan, K.,Menon, R.,Bhat, J.,Paul, B.,Iyer, H.,Hussein, S.,Tucker, J.A.,Vogtherr, M.,Embrey, K.J.,Mcmiken, H.,Prasad, S.,Gill, A.,Ugarkar, B.G.,Venkatraman, J.,Read, J.,Panda, M.
Structure Guided Lead Generation for M. Tuberculosis Thymidylate Kinase (Mtb Tmk): Discovery of 3-Cyanopyridone and 1,6-Naphthyridin-2-One as Potent Inhibitors.
J.Med.Chem., 58:753-, 2015

PubMed Abstract: 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 μM 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.

PubMed: 25486447
DOI: 10.1021/JM5012947

Experimental method

X-RAY DIFFRACTION (2.18 Å)