In vivo uptake of antisense oligonucleotide drugs predicted by ab initio quantum mechanical calculations.
Sci Rep
; 11(1): 6321, 2021 03 18.
Article
em En
| MEDLINE
| ID: mdl-33737567
ABSTRACT
Liver and kidney uptake and antisense activity is studied for a series of Locked Nucleic Acid (LNA) oligonucleotides with fully stereo-defined, internucleoside linkages. These stereo-specific phosphorothioates are made with a newly developed synthesis method and are being analyzed both theoretically and experimentally. Their structures are obtained theoretically by using many-body Schrödinger equations applied to a group of 11 stereo-defined LNA antisense oligonucleotides selected for biological experiments. The fully converged electronic structures were obtained from ab initio quantum calculations providing the specific electronic structures. One important result was the observation that the calculated electronic structure, represented by the iso-surface area of the electron density in Å2, correlated linearly with LNA oligonucleotide uptake in the liver and kidney. This study also shows that more complex biological phenomena, such as drug activity, will require more molecular and cellular identifiers than used here before a correlation can be found. Establishing biological correlations between quantum mechanical (QM) calculated structures and antisense oligonucleotides is novel, and this method may constitute new tools in drug discovery.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos
/
Oligonucleotídeos Antissenso
/
Rim
/
Fígado
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Dinamarca
País de publicação:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM