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Application of Computational Techniques in Pharmacy and Medicine pp 95–135Cite as

DNA Dependent DNA Polymerases as Targets for Low-Weight Molecular Inhibitors: State of Art and Prospects of Rational Design

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Part of the book series: Challenges and Advances in Computational Chemistry and Physics ((COCH,volume 17))

Abstract

DNA dependent DNA polymerases (DNA pols) are key enzymes providing the processes of DNA replication and reparation in living systems. Exceptional importance of DNA pols makes them to be attractive targets for specific low-molecular weight inhibitors, which can be used (and are actually used) as molecular tuning tools in molecular biology investigations, and as antineoplastic and antiviral drugs as well. Detailed comprehension of structural insights of pol–inhibitor interaction would not only give a possibility to design new drugs with highly selective activity with respect to the targeted polymerases, but would essentially extend our understanding of the structural basis of replicative/reparative processes as a whole. Several computational approaches including sophisticated modeling of protein structure, blind and site-oriented docking of inhibitor molecules, molecular dynamics simulation of pol–inhibitor complexes and free energy decomposition analysis are useful tools to improve the quality of structural analysis of pol–inhibitor interactions as well as selectivity of pols’ inhibitors developed de novo. Extended application of these methods is principle tendency in modern rational design, including search and/or design of new inhibitors of DNA polymerases.

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Notes

  1. 1.

    In the literature, these components of polymerase domain are also often named “domains”, which makes sense due to their different spatial folds. However, to avoid terminological confusion, we propose to consider them as subdomains of a unified polymerase domain.

  2. 2.

    Some researchers [31] consider the pyrophosphate analogs as a separate inhibitor group (product analogs’ group).

  3. 3.

    Now Accerlys Inc. has discounted a development and support of Insight II. Functionality of this software is transferred to Discovery Studio and Pipeline Pilot program suites.

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Acknowledgements

Author would like to sincere gratitude to Prof. Leonid Gorb, Prof. Alexei Kolezhuk, Oleg Lytuga, Tamara Limanska and Fedor Lavrik for their invaluable aid in preparing of this article.

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  1. High Technology Institute, Taras Shevchenko National University of Kyiv, 60, Volodymyrska St, 01601, Kyiv, Ukraine

    Alexey Yu. Nyporko

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Correspondence to Alexey Yu. Nyporko .

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  1. Department of Molecular Biophysics, Laboratory of Computational Structural Biology, Kiev, Ukraine

    Leonid Gorb

  2. Department of Molecular Structure and Chemoinformatics, A.V. Bogatsky Physical-Chemical Institute, National Academy of Sciences of Ukraine, Odessa, Ukraine

    Victor Kuz'min

  3. Department of Chemical Biology and Medicinal Chemistry, University of North Carolina, Laboratory for Molecular Modeling, Chapel Hill, North Carolina, USA

    Eugene Muratov

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Nyporko, A. (2014). DNA Dependent DNA Polymerases as Targets for Low-Weight Molecular Inhibitors: State of Art and Prospects of Rational Design. In: Gorb, L., Kuz'min, V., Muratov, E. (eds) Application of Computational Techniques in Pharmacy and Medicine. Challenges and Advances in Computational Chemistry and Physics, vol 17. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9257-8_4

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