Garg Saksham, Singh Japneet, Verma Smita Rastogi
Department of Biotechnology, Delhi Technological University, Delhi, 110042, India.
J Mol Model. 2023 Jan 26;29(2):55. doi: 10.1007/s00894-023-05454-2.
The mutations in the TP53 gene are the most frequent (50-60% of human cancer) genetic alterations in cancer cells, indicating the critical role of wild-type p53 in the regulation of cell proliferation and apoptosis upon oncogenic stress. Most missense mutations are clustered in the DNA-binding core domain, disrupting DNA binding ability. However, some mutations like Y220C occur outside the DNA binding domain and are associated with p53 structure destabilization. Overall, the results of these mutations are single amino acid substitutions in p53 and the production of dysfunctional p53 protein in large amounts, consequently allowing the escape of apoptosis and rapid progression of tumor growth. Thus, therapeutic targeting of mutant p53 in tumors to restore its wild-type tumor suppression activity has immense potential for translational cancer research. Various molecules have been discovered with modern scientific techniques to reactivate mutant p53 by reverting structural changes and/or DNA binding ability. These compounds include small molecules, various peptides, and phytochemicals. TP53 protein is long thought of as a potential target; however, its translation for therapeutic purposes is still in its infancy. The study comprehensively analyzed the therapeutic potential of small phytochemicals from Foeniculum vulgare (Fennel) with drug-likeness and capability to reactivate mutant p53 (Y220C) through molecular docking simulation. The docking study and the stable molecular dynamic simulations revealed juglalin (- 8.6 kcal/mol), retinol (- 9.14 kcal/mol), and 3-nitrofluoranthene (- 8.43 kcal/mol) significantly bind to the mutated site suggesting the possibility of drug designing against the Y220C mutp53. The study supports these compounds for further animal based in vivo and in vitro research to validate their efficacy.
For the purposes of drug repurposing, recently in-silico methods have presented with opportunity to rule out many compounds which have less probability to act as a drug based on their structural moiety and interaction with the target macromolecule. The study here utilizes molecular docking via Autodock 4.2.6 and molecular dynamics using Schrodinger 2021 to find potential therapeutic options which are capable to reactive the mutated TP53 protein.
TP53基因的突变是癌细胞中最常见的（占人类癌症的50 - 60%）基因改变，这表明野生型p53在致癌应激时对细胞增殖和凋亡的调节中起关键作用。大多数错义突变聚集在DNA结合核心结构域，破坏DNA结合能力。然而，一些突变如Y220C发生在DNA结合结构域之外，并与p53结构不稳定有关。总体而言，这些突变的结果是p53中单个氨基酸的替换以及大量功能失调的p53蛋白的产生，从而使得细胞逃避凋亡并导致肿瘤生长快速进展。因此，在肿瘤中靶向治疗突变型p53以恢复其野生型肿瘤抑制活性在转化癌症研究中具有巨大潜力。利用现代科学技术已经发现了各种分子，通过恢复结构变化和/或DNA结合能力来重新激活突变型p53。这些化合物包括小分子、各种肽和植物化学物质。长期以来，TP53蛋白一直被认为是一个潜在靶点；然而，其用于治疗目的的转化仍处于起步阶段。该研究通过分子对接模拟全面分析了来自小茴香（Foeniculum vulgare）的具有类药物特性且能够重新激活突变型p53（Y220C）的小型植物化学物质的治疗潜力。对接研究和稳定的分子动力学模拟显示胡桃素（- 8.6千卡/摩尔）、视黄醇（- 9.14千卡/摩尔）和3 - 硝基荧蒽（- 8.43千卡/摩尔）与突变位点有显著结合，这表明针对Y220C突变型p53进行药物设计的可能性。该研究支持对这些化合物进行进一步基于动物的体内和体外研究以验证其疗效。
为了进行药物再利用，最近的计算机模拟方法提供了一个机会，基于其结构部分和与靶标大分子的相互作用，排除许多不太可能作为药物的化合物。本研究利用Autodock 4.2.6进行分子对接，并使用Schrodinger 2021进行分子动力学，以寻找能够激活突变型TP53蛋白的潜在治疗选择。
