Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci 13, I-98168 Messina, Italy.
Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Viale Europa e Germaneto, I-88100 Catanzaro, Italy.
Molecules. 2021 Feb 19;26(4):1103. doi: 10.3390/molecules26041103.
Computer aided drug-design methods proved to be powerful tools for the identification of new therapeutic agents. We employed a structure-based workflow to identify new inhibitors targeting mTOR kinase at rapamycin binding site. By combining molecular dynamics (MD) simulation and pharmacophore modelling, a simplified structure-based pharmacophore hypothesis was built starting from the FKBP12-rapamycin-FRB ternary complex retrieved from RCSB Protein Data Bank (PDB code 1FAP). Then, the obtained model was used as filter to screen the ZINC biogenic compounds library, containing molecules derived from natural sources or natural-inspired compounds. The resulting hits were clustered according to their similarity; moreover, compounds showing the highest pharmacophore fit-score were chosen from each cluster. The selected molecules were subjected to docking studies to clarify their putative binding mode. The binding free energy of the obtained complexes was calculated by MM/GBSA method and the hits characterized by the lowest ΔG values were identified as potential mTOR inhibitors. Furthermore, the stability of the resulting complexes was studied by means of MD simulation which revealed that the selected compounds were able to form a stable ternary complex with FKBP12 and FRB domain, thus underlining their potential ability to inhibit mTOR with a rapamycin-like mechanism.
计算机辅助药物设计方法已被证明是识别新治疗剂的有力工具。我们采用基于结构的工作流程，针对雷帕霉素结合位点的 mTOR 激酶识别新的抑制剂。通过将分子动力学（MD）模拟和药效团建模相结合，从 RCSB 蛋白质数据库（PDB 代码 1FAP）中检索到的 FKBP12-雷帕霉素-FRB 三元复合物出发，构建了一个简化的基于结构的药效团假说。然后，将获得的模型用作筛选 ZINC 生物化合物库的过滤器，该库包含源自天然来源或天然启发化合物的分子。根据相似性对得到的命中进行聚类；此外，从每个簇中选择具有最高药效团拟合分数的化合物。选择的分子进行对接研究，以阐明其可能的结合模式。通过 MM/GBSA 方法计算获得的配合物的结合自由能，并确定具有最低 ΔG 值的命中为潜在的 mTOR 抑制剂。此外，通过 MD 模拟研究了所得配合物的稳定性，结果表明所选化合物能够与 FKBP12 和 FRB 结构域形成稳定的三元复合物，从而强调了它们以雷帕霉素样机制抑制 mTOR 的潜在能力。
