199
6 Quantum Chemical Approaches in Modeling the Structure of DNA …
We would like to mention here also the recent work by Nicoludis et al. [136],
where B3LYP/6-31G(d) calculations were successfully applied to the detailed study
of the structure of mesoporphyrin IX and N-methyl mesoporphyrin IX and possible
ways of binding of these specific G4 binders to human telomeric DNA sequence
d[AGGG(TTAGGG) 3 ] (Tel22).
6.4 Conclusions
Increasing understanding of the molecular basis of cancer has resulted in the identification of a number of novel molecular targets for anticancer drugs, including
telomerase and quadruplex nucleic acids that play critical role in the development
of tumors and other pathologies. The variability of DNA structures (from common
single- and double-stranded to more complex triplex and quadruplex forms) and
their conformational flexibility are the key factors in diverse biological functions
of DNA. Among possible DNA structures, G-quadruplexes deserve a special attention. The formation of these non-canonical assemblies in telomeres and some gene
promoter regions is a way of regulating the variety of basic biological processes in
a living cell. Taking into account important biological functions of G-quadruplexes,
the understanding of the structural, electronic and thermodynamic properties of
these DNA arrangements, their topology, dynamics, stability and mechanisms of
interaction with small molecules is of fundamental interest to biology, biomedical
science and pharmacology, as well as supramolecular chemistry and nanotechnology (see e.g. [78, 79, 137] and references therein). In this review we have discussed
biological functions and structural features of G-quadruplex DNA and quadruplexbinding compounds, and focused on molecular modelling methods being used in
the studies of these specific assemblies and their interaction with low-molecular
ligands, including metal cations and small organic molecules of potential interest
to pharmacology. As the structures of more and more quadruplexes and G4-ligand
complexes become available, modern computational approaches, along with biochemical and biophysical experimental methods, are increasingly considered indispensable tools in the study of DNA quadruplexes. These in silico tools allow deeper
insights into quadruplex structures and energetic features and, even more important,
predicting of many important properties of G4 and quadruplex-ligand complexes.
A number of successful anticancer drugs have already emerged from molecular
modelling studies. However, the real challenge in medicinal chemistry over the next
years will be the development of novel drugs that would not only be selective to
quadruplex over duplex nucleic acids to efficiently bind to G4 structures, but would
be also able to discriminate between the unique quadruplex topologies. Quantum
chemical computational approaches will undoubtedly be a key player in achieving
this exciting goal.
Acknowledgments Molecular visualization was performed with the UCSF Chimera package
developed by the Resource for Biocomputing, Visualization, and Informatics at the University of
California, San Francisco (supported by NIGMS P41-GM103311).
6 Quantum Chemical Approaches in Modeling the Structure of DNA …
We would like to mention here also the recent work by Nicoludis et al. [136],
where B3LYP/6-31G(d) calculations were successfully applied to the detailed study
of the structure of mesoporphyrin IX and N-methyl mesoporphyrin IX and possible
ways of binding of these specific G4 binders to human telomeric DNA sequence
d[AGGG(TTAGGG) 3 ] (Tel22).
6.4 Conclusions
Increasing understanding of the molecular basis of cancer has resulted in the identification of a number of novel molecular targets for anticancer drugs, including
telomerase and quadruplex nucleic acids that play critical role in the development
of tumors and other pathologies. The variability of DNA structures (from common
single- and double-stranded to more complex triplex and quadruplex forms) and
their conformational flexibility are the key factors in diverse biological functions
of DNA. Among possible DNA structures, G-quadruplexes deserve a special attention. The formation of these non-canonical assemblies in telomeres and some gene
promoter regions is a way of regulating the variety of basic biological processes in
a living cell. Taking into account important biological functions of G-quadruplexes,
the understanding of the structural, electronic and thermodynamic properties of
these DNA arrangements, their topology, dynamics, stability and mechanisms of
interaction with small molecules is of fundamental interest to biology, biomedical
science and pharmacology, as well as supramolecular chemistry and nanotechnology (see e.g. [78, 79, 137] and references therein). In this review we have discussed
biological functions and structural features of G-quadruplex DNA and quadruplexbinding compounds, and focused on molecular modelling methods being used in
the studies of these specific assemblies and their interaction with low-molecular
ligands, including metal cations and small organic molecules of potential interest
to pharmacology. As the structures of more and more quadruplexes and G4-ligand
complexes become available, modern computational approaches, along with biochemical and biophysical experimental methods, are increasingly considered indispensable tools in the study of DNA quadruplexes. These in silico tools allow deeper
insights into quadruplex structures and energetic features and, even more important,
predicting of many important properties of G4 and quadruplex-ligand complexes.
A number of successful anticancer drugs have already emerged from molecular
modelling studies. However, the real challenge in medicinal chemistry over the next
years will be the development of novel drugs that would not only be selective to
quadruplex over duplex nucleic acids to efficiently bind to G4 structures, but would
be also able to discriminate between the unique quadruplex topologies. Quantum
chemical computational approaches will undoubtedly be a key player in achieving
this exciting goal.
Acknowledgments Molecular visualization was performed with the UCSF Chimera package
developed by the Resource for Biocomputing, Visualization, and Informatics at the University of
California, San Francisco (supported by NIGMS P41-GM103311).