Structure Guided Lead Generation for M. tuberculosis Thymidylate Kinase (Mtb TMK): Discovery of 3-Cyanopyridone and 1,6-Naphthyridin-2-one as Potent Inhibitors
| Autor: | Rajesh Kalkhambkar, Bheemarao G. Ugarkar, Jon Read, Martin Vogtherr, Beena Paul, Swati Prasad, Adrian Liam Gill, Shantika Bhat, Helen H.J. McMiken, Maruti Naik, Jyothi Bhat, Julie A. Tucker, Kevin J. Embrey, Begur Vasanthkumar Varun, Balachandra Bandodkar, Rani Menon, Syeed Hussein, Janani Venkatraman, Kannan Murugan, Harini Iyer, Anandkumar Raichurkar, Manoranjan Panda |
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| Rok vydání: | 2014 |
| Předmět: |
chemistry.chemical_classification
Binding Sites Magnetic Resonance Spectroscopy Ligand efficiency Tuberculosis DNA synthesis Chemistry Stereochemistry Mycobacterium tuberculosis Thymidylate Synthase Hit to lead medicine.disease Thymidylate kinase In vitro High-Throughput Screening Assays Structure-Activity Relationship Enzyme Biochemistry Drug Discovery medicine Humans Molecular Medicine Transferase Enzyme Inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 58:753-766 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm5012947 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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