Journal article
Quantum Mechanical Studies of DNA and LNA
Santaris Pharma A/S1
Department of Chemistry, Technical University of Denmark2
Physical and Biophysical Chemistry, Department of Chemistry, Technical University of Denmark3
Department of Physics, Technical University of Denmark4
Biophysics and Fluids, Department of Physics, Technical University of Denmark5
Quantum mechanical (QM) methodology has been employed to study the structure activity relations of DNA and locked nucleic acid (LNA). The QM calculations provide the basis for construction of molecular structure and electrostatic surface potentials from molecular orbitals. The topologies of the electrostatic potentials were compared among model oligonucleotides, and it was observed that small structural modifications induce global changes in the molecular structure and surface potentials.
Since ligand structure and electrostatic potential complementarity with a receptor is a determinant for the bonding pattern between molecules, minor chemical modifications may have profound changes in the interaction profiles of oligonucleotides, possibly leading to changes in pharmacological properties.
The QM modeling data can be used to understand earlier observations of antisense oligonucleotide properties, that is, the observation that small structural changes in oligonucleotide composition may lead to dramatic shifts in phenotypes. These observations should be taken into account in future oligonucleotide drug discovery, and by focusing more on non RNA target interactions it should be possible to utilize the exhibited property diversity of oligonucleotides to produce improved antisense drugs.
Language: | English |
---|---|
Publisher: | Mary Ann Liebert, Inc. |
Year: | 2014 |
Pages: | 139-148 |
ISSN: | 21593345 , 21593337 , 15578526 and 15454576 |
Types: | Journal article |
DOI: | 10.1089/nat.2013.0465 |
ORCIDs: | Shim, Irene |
03502, Genetics - General 04500, Mathematical biology and statistical methods 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines 10515, Biophysics - Biocybernetics 12512, Pathology - Therapy 22002, Pharmacology - General Biochemistry and Molecular Biophysics Computational Biology DNA Models and Simulations Molecular Genetics Original Articles Pharmacology RNA antisense drug interaction drug discovery electrostatic potential ligand structure locked nucleic acid LNA oligonucleotides pharmacological property quantum mechanical modeling mathematical and computer techniques