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通过虚拟筛选、分子动力学模拟和ADMET分析鉴定慢性髓性白血病的双重天然抑制剂

Identification of Dual Natural Inhibitors for Chronic Myeloid Leukemia by Virtual Screening, Molecular Dynamics Simulation and ADMET Analysis.

作者信息

Kumar Himansu, Raj Utkarsh, Srivastava Swati, Gupta Saurabh, Varadwaj Pritish K

机构信息

Indian Institute of Information Technology Allahabad, Allahabad, UP, 211012, India.

Lovely Professional University, Jalandhar, Punjab, 144411, India.

出版信息

Interdiscip Sci. 2016 Sep;8(3):241-52. doi: 10.1007/s12539-015-0118-7. Epub 2015 Aug 22.

Abstract

Chronic myeloid leukemia (CML) is a disease of bone marrow stem cells caused by excessive growth and accumulation of granulocytes in the blood. Aberrant expression of the BCR-ABL proteins in bone marrow stem cells have found out in 95 % cases of CML. Tyrosine Kinase domains (SH2 and SH3) of BCR-ABL proteins are the potent targets to inhibit the process. Initially, imatinib is preferred as an efficient inhibitor to control functional activity of disease. Recently, it has been reported that the advanced stage of CML developed resistance against imatinib. In continuation, dasatinib is the first drug to combat against this disease by targeting multiple receptors and proven better as compared to imatinib. Here, an attempt has been made to identify similar analogs of dasatinib. Virtual screening was performed against various natural compound databases to get some potent natural compounds which are able to inhibit more than one receptor. Binding affinity of screened natural compounds was compared with some of the well-known inhibitors like imatinib, dasatinib, nilotinib etc., by analyzing their docking score and binding efficiency with the receptor. Stability of the best ligand-receptor complex was checked by performing 10 ns molecular dynamics simulation. ADMET properties of the obtained screened compounds were analyzed to check drug like property. Based on the aforementioned analysis, it has been suggested that these screened potent compounds are capable to inhibit multiple receptor proteins like ABL and SRC and consequently combat against the deadly disease CML.

摘要

慢性髓性白血病(CML)是一种骨髓干细胞疾病,由血液中粒细胞过度生长和积累引起。在95%的CML病例中发现骨髓干细胞中BCR-ABL蛋白表达异常。BCR-ABL蛋白的酪氨酸激酶结构域(SH2和SH3)是抑制该过程的有效靶点。最初,伊马替尼作为一种有效的抑制剂被优先用于控制疾病的功能活性。最近,有报道称CML晚期对伊马替尼产生了耐药性。接着,达沙替尼是第一种通过靶向多种受体来对抗这种疾病的药物,并且已证明比伊马替尼效果更好。在此,已尝试鉴定达沙替尼的类似物。针对各种天然化合物数据库进行虚拟筛选,以获得一些能够抑制多种受体的有效天然化合物。通过分析筛选出的天然化合物与伊马替尼、达沙替尼、尼洛替尼等一些知名抑制剂的对接分数和与受体的结合效率,比较它们的结合亲和力。通过进行10纳秒的分子动力学模拟来检查最佳配体-受体复合物的稳定性。分析所得筛选化合物的ADMET性质以检查其类药性质。基于上述分析,已表明这些筛选出的有效化合物能够抑制ABL和SRC等多种受体蛋白,从而对抗致命疾病CML。

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