High throughput screening, docking, and molecular dynamics studies to identify potential inhibitors of human calcium/calmodulin-dependent protein kinase IV
High throughput screening, docking, and molecular dynamics studies to identify potential inhibitors of human calcium/calmodulin-dependent protein kinase IV
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DOI：
10.1080/07391102.2018.1479310
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发表时间：
2019-01-01
影响因子：
4.4
通讯作者：
Hassan, Md. Imtaiyaz
中科院分区：
文献类型：
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作者：
Beg, Anam;Khan, Faez Iqbal;Hassan, Md. Imtaiyaz
钙/钙调蛋白依赖性蛋白激酶IV（CAMKIV）与包括癌症和神经退行性疾病在内的许多疾病相关，因此被认为是潜在的药物靶点。在这里，我们已经采用了三维结构的知识CAMKIV，以确定新的抑制剂可能的治疗干预。我们对锌数据库的12，500种天然化合物进行了虚拟高通量筛选，以筛选最佳的CAMKIV抑制剂。随后，选择具有显著对接分数（-11.6至-10.0kcal/mol）的40个化合物，并通过Lipinski规则和药物相似性参数进一步筛选，以获得最佳的CAMKIV抑制剂。对接结果表明配体与CAMKIV的激酶结构域的疏水腔结合并形成大量的非共价相互作用。通过分子动力学模拟研究了4个具有良好亲和性和药物相似性的化合物ZINC 02098378、ZINC 12866674、ZINC 04293413和ZINC 13403020的作用机制和蛋白质-配体复合物的稳定性。我们的观察清楚地表明，这些选择的配体可以进一步用于治疗干预，以解决CAMKIV相关疾病。Sarma
Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is associated with many diseases including cancer and neurodegenerative disorders and thus being considered as a potential drug target. Here, we have employed the knowledge of three-dimensional structure of CAMKIV to identify new inhibitors for possible therapeutic intervention. We have employed virtual high throughput screening of 12,500 natural compounds of Zinc database to screen the best possible inhibitors of CAMKIV. Subsequently, 40 compounds which showed significant docking scores (-11.6 to -10.0kcal/mol) were selected and further filtered through Lipinski rule and drug likeness parameter to get best inhibitors of CAMKIV. Docking results are indicating that ligands are binding to the hydrophobic cavity of the kinase domain of CAMKIV and forming a significant number of non-covalent interactions. Four compounds, ZINC02098378, ZINC12866674, ZINC04293413, and ZINC13403020, showing excellent binding affinity and drug likeness were subjected to molecular dynamics simulation to evaluate their mechanism of interaction and stability of protein-ligand complex. Our observations clearly suggesting that these selected ligands may be further employed for therapeutic intervention to address CAMKIV associated diseases.Communicated by Ramaswamy H. Sarma