Quantum Chemical Studies Employing an<i>Ab Initio</i>Combination Approach on the Binding of the Bis-Benzimidazole Hoechst 33258 to the Minor Groove of DNA

Am, Sapse; Sapse, Danielle; Dc, Jain; Jw, Lown

doi:10.1080/07391102.1995.10508781

Cited by 3 publications

(1 citation statement)

References 23 publications

(14 reference statements)

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“…Although the inhibitory effect appears to result from direct interaction of the compounds with the enzymes, some action at the level of the RNA and/or DNA substrates cannot be unequivocally excluded. Various benzimidazole analogues have been demonstrated to intercalate into dsRNA and/or dsDNA structures [38–40], and may modify their properties as substrates for NTPase/helicases, as is the case with some imidazo[4,5‐d]pyridazine derivatives [41]. Moreover, the interaction of these compounds with RNA and/or DNA appears to be dependent on the base sequence of the polynucleotide [42].…”

Section: Discussionmentioning

confidence: 99%

Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses

Borowski

Deinert

Schalinski

et al. 2003

European Journal of Biochemistry

117

108

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A search has been initiated for lead inhibitors of the nonstructural protein 3 (NS3)-associated NTPase/helicase activities of hepatitis C virus, the related West Nile virus, Japanese encephalitis virus and the human mitochondrial Suv3 enzyme. Random screening of a broad range of unrelated low-molecular mass compounds, employing both RNA and DNA substrates, revealed that 4,5,6,7-tetrabromobenzotriazole (TBBT) hitherto known as a potent highly selective inhibitor of protein kinase 2, is a good inhibitor of the helicase, but not NTPase, activity of hepatitis C virus NTPase/helicase. The IC 50 is approximately 20 lM with a DNA substrate, but only 60 lM with an RNA substrate. Several related analogues of TBBT were enzymeand/or substrate-specific inhibitors. For example, 5,6-dichloro-1-(b-D-ribofuranosyl)benzotriazole (DRBT) was a good, and selective, inhibitor of the West Nile virus enzyme with an RNA substrate (IC 50 0.3 lM), but much weaker with a DNA substrate (IC 50 3 lM). Preincubation of the enzymes, but not substrates, with DRBT enhanced inhibitory potency, e.g. the IC 50 vs the hepatitis C virus helicase activity was reduced from 1.5 to 0.1 lM. No effect of preincubation was noted with TBBT, suggesting a different mode of interaction with the enzyme. The tetrachloro congener of TBBT, 4,5,6,7,-tetrachlorobenzotriazole (TCBT; a much weaker inhibitor of casein kinase 2) is also a much weaker inhibitor than TBBT of all four helicases. Kinetic studies, supplemented by comparison of ATP-binding sites, indicated that, unlike the case with casein kinase 2, the mode of action of the inhibitors vs the helicases is not by interaction with the catalytic ATP-binding site, but rather by occupation of an allosteric nucleoside/nucleotide binding site. The halogeno benzimidazoles and benzotriazoles included in this study are excellent lead compounds for the development of more potent inhibitors of hepatitis C virus and other viral NTPase/helicases.

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Section: Discussionmentioning

confidence: 99%