95
Chapter 4
DNA Dependent DNA Polymerases as Targets
for Low-Weight Molecular Inhibitors: State
of Art and Prospects of Rational Design
Alexey Yu. Nyporko
© Springer Science+Business Media Dordrecht 2014
L. Gorb et al. (eds.), Application of Computational Techniques in Pharmacy and Medicine,
Challenges and Advances in Computational Chemistry and Physics 17,
DOI 10.1007/978-94-017-9257-8_4
A. Yu. Nyporko ()
High Technology Institute, Taras Shevchenko National University of Kyiv, 60,
Volodymyrska St, 01601 Kyiv, Ukraine
e-mail: anyporko@univ.net.ua; dfnalex@gmail.com
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.
4.1 Introduction
Life on Earth would be impossible without the processes of reproduction, storage,
repairing and transmission of hereditary information in a series of generations. Key
factors providing these processes are DNA dependent DNA polymerases (DNA
pols). These enzymes catalyze the synthesis of a new DNA chain based on preexisting DNA molecule, according to the principle of complementarity of nitrogenous bases in the “mother” and “daughter” chains. Such process of matrix DNA
synthesis is known as DNA replication. The elementary chemical act of catalysis
Chapter 4
DNA Dependent DNA Polymerases as Targets
for Low-Weight Molecular Inhibitors: State
of Art and Prospects of Rational Design
Alexey Yu. Nyporko
© Springer Science+Business Media Dordrecht 2014
L. Gorb et al. (eds.), Application of Computational Techniques in Pharmacy and Medicine,
Challenges and Advances in Computational Chemistry and Physics 17,
DOI 10.1007/978-94-017-9257-8_4
A. Yu. Nyporko ()
High Technology Institute, Taras Shevchenko National University of Kyiv, 60,
Volodymyrska St, 01601 Kyiv, Ukraine
e-mail: anyporko@univ.net.ua; dfnalex@gmail.com
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.
4.1 Introduction
Life on Earth would be impossible without the processes of reproduction, storage,
repairing and transmission of hereditary information in a series of generations. Key
factors providing these processes are DNA dependent DNA polymerases (DNA
pols). These enzymes catalyze the synthesis of a new DNA chain based on preexisting DNA molecule, according to the principle of complementarity of nitrogenous bases in the “mother” and “daughter” chains. Such process of matrix DNA
synthesis is known as DNA replication. The elementary chemical act of catalysis