CMML-Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Napaam, Sonitpur, Assam 784028, India.
HPC - Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Panchavati, Pashan, Pune 411008, India.
Langmuir. 2024 Oct 15;40(41):21407-21426. doi: 10.1021/acs.langmuir.4c02171. Epub 2024 Oct 6.
Antisense medications treat diseases that cannot be treated using traditional pharmacological technologies. Nucleotide monomers of bare and phosphorothioate (PS)-modified LNA, N-MeO-amino-BNA, 2',4'-BNA[NH], 2',4'-BNA[NMe], and N-Me-aminooxy-BNA antisense modifications were considered for a detailed DFT-based quantum chemical study to estimate their molecular-level structural and electronic properties. Oligomer hybrid duplex stability is described by performing an elaborate MD simulation study by incorporating the PS-LNA and PS-BNA antisense modifications onto 14-mer ASO/RNA hybrid gapmer type duplexes targeting protein PTEN mRNA nucleic acid sequence (5'--3'/3'-GAAUCGUGACCGGA-5'). Replica sets of MD simulations were performed accounting to two data sets, each set simulated for 1 μs simulation time. Bulk properties of oligomers are regulated by the chemical properties of their monomers. As such, the primary goal of this work focused on establishing an organized connection between the monomeric BNA nucleotide's electronic effects observed in DFT studies and the macroscopic behavior of the BNA antisense oligomers, as observed in MD simulations. The results from this study predicted that spatial orientation of MO-isosurfaces of the BNA nucleotides are concentrated in the nucleobase region. These BNA nucleotides may become less accessible for various electronic interactions when coupled as ASOs forming duplexes with target RNAs and when the ASO/RNA duplexes further bind with the RNase H. Understanding such electronic interactions is crucial to design superior antisense modifications with specific electronic properties. Also, for the particular nucleic acid sequence solvation of the duplexes although were higher compared to the natural oligonucleotides, their binding energies being relatively lower may lead to decreased antisense activity compared to existing analogs such as the LNAs and MOEs. Fine tuning these BNAs to obtain superior binding affinity is thus a necessity.
反义药物治疗不能使用传统药理学技术治疗的疾病。研究了裸露核苷酸单体和硫代磷酸酯 (PS)-修饰的 LNA、N-MeO-氨基-BNA、2'，4'-BNA[NH]、2'，4'-BNA[NMe]和 N-Me-氨基氧基-BNA 反义修饰物，以进行详细的基于 DFT 的量子化学研究，以估计它们的分子水平结构和电子性质。通过对靶向蛋白质 PTEN mRNA 核酸序列（5'--3'/3'-GAAUCGUGACCGGA-5'）的 14 -mer ASO/RNA 杂交 gapmer 型双链体进行精细的 MD 模拟研究，描述了寡聚物杂交双链体的稳定性。模拟时间为 1 μs。模拟了两个数据集的 replica 集。寡聚物的体性质受其单体的化学性质调节。因此，这项工作的主要目标集中在建立 DFT 研究中观察到的 BNA 核苷酸的电子效应与 MD 模拟中观察到的 BNA 反义寡聚物的宏观行为之间的有序联系。这项研究的结果表明，BNA 核苷酸的 MO 等位面的空间取向集中在核碱基区域。当这些 BNA 核苷酸与靶 RNA 形成双链体时，以及当 ASO/RNA 双链体进一步与 RNase H 结合时，它们可能变得不易受到各种电子相互作用的影响。了解这种电子相互作用对于设计具有特定电子性质的卓越反义修饰物至关重要。此外，尽管与天然寡核苷酸相比，双链体的特定核酸序列的溶剂化作用更高，但它们的结合能相对较低，与现有类似物（如 LNAs 和 MOEs）相比，可能导致反义活性降低。因此，需要对这些 BNA 进行微调以获得更高的结合亲和力。
