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Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

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Summary

Using the X-ray crystal structure of the human topoisomerase I (top1) – DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the −1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.

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Authors and Affiliations

  1. Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University, SK-83232, Bratislava, Slovakia

    Viktor Kettmann

  2. Department of Pharmacognosy and Botany, Faculty of Pharmacy, Comenius University, SK-83232, Bratislava, Slovakia

    Daniela Košt’álová

  3. Department of Pharmaceutical Chemistry, Heinrich-Heine University, D-40225, Düsseldorf, Germany

    Hans-Dieter Höltje

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  1. Viktor Kettmann
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  2. Daniela Košt’álová
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  3. Hans-Dieter Höltje
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Correspondence to Viktor Kettmann.

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Kettmann, V., Košt’álová, D. & Höltje, HD. Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model. J Comput Aided Mol Des 18, 785–796 (2004). https://doi.org/10.1007/s10822-004-7878-1

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