- Phenylthiomethyl Ketone-Based Fragments Show Selective and Irreversible Inhibition of Enteroviral 3C Proteases
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Lead structure discovery mainly focuses on the identification of noncovalently binding ligands. Covalent linkage, however, is an essential binding mechanism for a multitude of successfully marketed drugs, although discovered by serendipity in most cases. We present a concept for the design of fragments covalently binding to proteases. Covalent linkage enables fragment binding unrelated to affinity to shallow protein binding sites and at the same time allows differentiated targeted hit verification and binding location verification through mass spectrometry. We describe a systematic and rational computational approach for the identification of covalently binding fragments from compound collections inhibiting enteroviral 3C protease, a target with high therapeutic potential. By implementing reactive groups potentially forming covalent bonds as a chemical feature in our 3D pharmacophore methodology, covalent binders were discovered by high-throughput virtual screening. We present careful experimental validation of the virtual hits using enzymatic assays and mass spectrometry unraveling a novel, previously unknown irreversible inhibition of the 3C protease by phenylthiomethyl ketone-based fragments. Subsequent synthetic optimization through fragment growing and reactivity analysis against catalytic and noncatalytic cysteines revealed specific irreversible 3C protease inhibition.
- Schulz, Robert,Atef, Amira,Becker, Daniel,Gottschalk, Franziska,Tauber, Carolin,Wagner, Stefan,Arkona, Christoph,Abdel-Hafez, Atef A.,Farag, Hassan H.,Rademann, J?rg,Wolber, Gerhard
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supporting information
p. 1218 - 1230
(2018/02/17)
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- Production of anticancer polyenes through precursor-directed biosynthesis
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The biosynthesis of the pyrrolyl moiety of the fungal metabolite rumbrin originates from pyrrole-2-carboxylic acid. In an effort to produce novel derivatives with enhanced biological activity a series of substituted pyrrole-2-carboxylates were synthesised
- Clark, Benjamin R.,O'Connor, Stephen,Fox, Deirdre,Leroy, Jacques,Murphy, Cormac D.
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experimental part
p. 6306 - 6311
(2011/10/10)
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- Preparation of alkyl-substituted indoles in the benzene portion. Part 15. Asymmetric synthesis of (+)-duocarmycin SA using novel procedure for preparation of hydroxyindoles
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An asymmetric total synthesis of natural (+)-duocarmycin SA (1) starting from L-malic acid (7) was achieved as shown in Chart 5, establishing firmly the absolute configuration of 1. In order to find suitable reaction conditions for the key step, i.e., the formation of an alkoxyindole derivative, model compounds 9 and 40 were synthesized and two acetalization conditions using i) 2-ethyl-2-methyl-1,3-dioxane and boron trifluoride etherate, and ii) 1,3-bis(trimethylsilyloxy)propane and trimethylsilyl trifiate were found to be effective. The former conditions were successfully applied to the total synthesis and 49b was prepared from 48 in 54% yield. Further elaborations including i) Curtius rearrangement of 53b to 56, and it) cleavage of the primary benzyloxy group in the presence of the secondary one in its close vicinity (56→57) led to the relay compound 62, whose conversion to 1 has already been accomplished.
- Muratake, Hideaki,Matsumura, Naoshige,Natsume, Mitsutaka
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p. 559 - 571
(2007/10/03)
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