Parate Shraddha, Kumar Vikas, Lee Gihwan, Rampogu Shailima, Hong Jong Chan, Lee Keun Woo
Division of Applied Life Science, Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea.
Division of Life Sciences, Department of Bio & Medical Big Data (BK21 Program), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea.
Pharmaceuticals (Basel). 2021 Mar 21;14(3):282. doi: 10.3390/ph14030282.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase portraying a quintessential role in cellular proliferation and survival. Aberrations in the mTOR signaling pathway have been reported in numerous cancers including thyroid, lung, gastric and ovarian cancer, thus making it a therapeutic target. To attain this objective, an in silico investigation was designed, employing a pharmacophore modeling approach. A structure-based pharmacophore (SBP) model exploiting the key features of a selective mTOR inhibitor, Torkinib directed at the ATP-binding pocket was generated. A Marine Natural Products (MNP) library was screened using SBP model as a query. The retrieved compounds after consequent drug-likeness filtration were subjected to molecular docking with mTOR, thus revealing four MNPs with better scores than Torkinib. Successive refinement via molecular dynamics simulations demonstrated that the hits formed crucial interactions with key residues of the pocket. Furthermore, the four identified hits exhibited good binding free energy scores through MM-PBSA calculations and the subsequent in silico toxicity assessments displayed three hits deemed essentially non-carcinogenic and non-mutagenic. The hits presented in this investigation could act as potent ATP-competitive mTOR inhibitors, representing a platform for the future discovery of drugs from marine natural origin.
雷帕霉素的哺乳动物靶点（mTOR）是一种丝氨酸/苏氨酸激酶，在细胞增殖和存活中起着至关重要的作用。在包括甲状腺癌、肺癌、胃癌和卵巢癌在内的众多癌症中，均报道了mTOR信号通路的异常，因此使其成为一个治疗靶点。为实现这一目标，设计了一项基于计算机的研究，采用药效团建模方法。利用选择性mTOR抑制剂托瑞替尼针对ATP结合口袋的关键特征，生成了一个基于结构的药效团（SBP）模型。以SBP模型作为查询工具，对海洋天然产物（MNP）库进行筛选。经过后续类药性质筛选后得到的化合物与mTOR进行分子对接，从而揭示出四种得分优于托瑞替尼的MNP。通过分子动力学模拟进行的连续优化表明，这些命中化合物与口袋中的关键残基形成了关键相互作用。此外，通过MM-PBSA计算，这四种鉴定出的命中化合物表现出良好的结合自由能得分，随后的计算机毒性评估显示，三种命中化合物被认为基本无致癌性和致突变性。本研究中呈现的这些命中化合物可作为有效的ATP竞争性mTOR抑制剂，为未来从海洋天然来源发现药物提供了一个平台。
