Ashley Carolyn N, Broni Emmanuel, Pena-Martinez Michelle, Wood Chanyah M, Kwofie Samuel K, Miller Whelton A
Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA.
Department of Molecular Pharmacology & Neuroscience, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA.
Int J Mol Sci. 2025 Apr 25;26(9):4075. doi: 10.3390/ijms26094075.
Mesothelioma is a rare and aggressive cancer linked to asbestos exposure and characterized by rapid metastasis and poor prognosis. Inhibition of adenosine deaminase acting on dsRNA 2 (ADAR2) RNA binding but not ADAR2 editing has shown antitumor effects in mesothelioma. Natural compounds from the Traditional Chinese Medicine (TCM) database were docked to the RNA-binding interface of ADAR2's second dsRNA binding domain (dsRBD2), and their drug-likeness and predicted safety were assessed. Eight ligands (ZINC000085597263, ZINC000085633079, ZINC000014649947, ZINC000034512861, ZINC000070454124, ZINC000085594944, ZINC000085633008, and ZINC000095909822) showed high binding affinity to dsRBD2 from molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. Protein-ligand interactions were analyzed to identify key residues contributing to these binding affinities. Molecular dynamics (MD) simulations of dsRBD-ligand-RNA complexes revealed that four compounds (ZINC000085597263, ZINC000085633079, ZINC000014649947, and ZINC000034512861) had negative binding affinities to dsRBD2 in the presence of the RNA substrate GluR-2. Key residues, including Val164, Met165, Lys209, and Lys212, were crucial for ligand binding, even with RNA present, suggesting these compounds could inhibit dsRBD2's RNA-binding function. The predicted biological activities of these compounds indicate potential anticancer properties, particularly for the treatment of mesothelioma. These compounds are structurally similar to known anti-mesothelioma agents or anticancer drugs, highlighting their therapeutic potential. Current mesothelioma treatments are limited. Optimization of these compounds, alone or in combination with current therapeutics, has potential for mesothelioma treatment. Additionally, five high-quality full-length ADAR2 models were developed. These models provide insights into ADAR2 function, mutation impacts, and potential areas for protein engineering to enhance stability, RNA-binding specificity, or protein interactions, particularly concerning dimerization or complex formation with other proteins and RNAs.
间皮瘤是一种罕见且侵袭性强的癌症，与接触石棉有关，其特点是转移迅速且预后不良。抑制作用于双链RNA 2（ADAR2）的腺苷脱氨酶的RNA结合而非ADAR2编辑，已在间皮瘤中显示出抗肿瘤作用。将来自中药（TCM）数据库的天然化合物对接至ADAR2第二个双链RNA结合结构域（dsRBD2）的RNA结合界面，并评估其类药性和预测的安全性。通过分子力学泊松-玻尔兹曼表面积（MM/PBSA）计算，8种配体（ZINC000085597263、ZINC000085633079、ZINC000014649947、ZINC000034512861、ZINC000070454124、ZINC000085594944、ZINC000085633008和ZINC000095909822）对dsRBD2显示出高结合亲和力。分析了蛋白质-配体相互作用，以确定对这些结合亲和力有贡献的关键残基。双链RNA结合结构域-配体-RNA复合物的分子动力学（MD）模拟表明，在存在RNA底物GluR-2的情况下，4种化合物（ZINC000085597263、ZINC000085633079、ZINC000014649947和ZINC000034512861）对dsRBD2具有负结合亲和力。关键残基，包括Val164、Met165、Lys209和Lys212，即使在有RNA存在的情况下，对配体结合也至关重要，这表明这些化合物可抑制dsRBD2的RNA结合功能。这些化合物预测的生物学活性表明其具有潜在的抗癌特性，特别是用于治疗间皮瘤。这些化合物在结构上与已知的抗间皮瘤药物或抗癌药物相似，突出了它们的治疗潜力。目前间皮瘤的治疗方法有限。单独或与现有疗法联合优化这些化合物，对间皮瘤治疗具有潜力。此外，还开发了5个高质量的全长ADAR2模型。这些模型为ADAR2的功能、突变影响以及蛋白质工程的潜在领域提供了见解，以增强稳定性、RNA结合特异性或蛋白质相互作用，特别是关于与其他蛋白质和RNA的二聚化或复合物形成。
