Grupo de Investigación en Química y Biología, Departamento de Química y Biología, Universidad del Norte, Cra 51B, Km 5, vía Puerto Colombia, Barranquilla 081007, Colombia.
Grupo de Química computacional y teórica (QCT-USFQ) & instituto de Simulación Computacional (ISC-USF), Departamento de Ingeniería Química, Colegio Politécnico de Ciencias e Ingeniería, Diego de Robles, y vía Interoceánica, Universidad San Francisco de Quito, Quito 170901, Ecuador.
Molecules. 2019 Dec 19;25(1):24. doi: 10.3390/molecules25010024.
The antileukemia cancer activity of organic compounds analogous to ellipticine representes a critical endpoint in the understanding of this dramatic disease. A molecular modeling simulation on a dataset of 23 compounds, all of which comply with Lipinski's rules and have a structure analogous to ellipticine, was performed using the quantitative structure activity relationship (QSAR) technique, followed by a detailed docking study on three different proteins significantly involved in this disease (PDB IDs: SYK, PI3K and BTK). As a result, a model with only four descriptors (HOMO, softness, AC1RABAMBID, and TS1KFABMID) was found to be robust enough for prediction of the antileukemia activity of the compounds studied in this work, with an R of 0.899 and Q of 0.730. A favorable interaction between the compounds and their target proteins was found in all cases; in particular, compounds and showed high activity and binding free energy values of around -10 kcal/mol. Theses compounds were evaluated in detail based on their molecular structure, and some modifications are suggested herein to enhance their biological activity. In particular, compounds , , , and are indicated as possible new, potent ellipticine derivatives to be synthesized and biologically tested.
有机化合物的抗白血病抗癌活性类似于椭圆体素，这代表着对这种戏剧性疾病的理解的一个关键终点。对符合 Lipinski 规则且结构类似于椭圆体素的 23 种化合物数据集进行了定量构效关系 (QSAR) 技术的分子建模模拟，然后对三种不同的蛋白质（PDB IDs：SYK、PI3K 和 BTK）进行了详细的对接研究。结果，发现只有四个描述符（HOMO、柔软度、AC1RABAMBID 和 TS1KFABMID）的模型足以用于预测本工作中研究的化合物的抗白血病活性，其 R 为 0.899，Q 为 0.730。在所有情况下，都发现化合物与其靶蛋白之间存在有利的相互作用；特别是化合物 和 表现出高活性和结合自由能值约为-10 kcal/mol。根据这些化合物的分子结构对它们进行了详细评估，并在此提出了一些改进建议以提高它们的生物活性。特别是，化合物 、 、 和 被认为是可能的新的、有效的椭圆体素衍生物，有待合成和生物测试。
