Roche Innovation Center Copenhagen, Fremtidsvej 3, 2970, Hoersholm, Denmark.
Department of Chemistry, B-206-DTU, The Technical University of Denmark, 2800, Lyngby, Denmark.
Sci Rep. 2021 Mar 18;11(1):6321. doi: 10.1038/s41598-021-85453-6.
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 Å, 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.
研究了一系列具有完全立体定义的、核苷间键的锁核酸（LNA）寡核苷酸的肝、肾摄取和反义活性。这些立体专一性的硫代磷酸酯是用新开发的合成方法制备的，并进行了理论和实验分析。它们的结构是通过对一组为生物实验选择的 11 个立体定义的 LNA 反义寡核苷酸应用多体薛定谔方程理论上获得的。完全收敛的电子结构是通过从头算量子计算获得的，提供了特定的电子结构。一个重要的结果是观察到，由电子密度在 Å 的等表面积表示的计算电子结构与肝和肾中的 LNA 寡核苷酸摄取呈线性相关。这项研究还表明，在找到相关性之前，将需要比这里使用的更多的分子和细胞标识符来研究更复杂的生物现象，如药物活性。在量子力学（QM）计算结构和反义寡核苷酸之间建立生物学相关性是新颖的，这种方法可能构成药物发现的新工具。
