High‐throughput Docking and Molecular Dynamics Simulations towards the Identification of Novel Peptidomimetic Inhibitors against CDC7
High‐throughput Docking and Molecular Dynamics Simulations towards the Identification of Novel Peptidomimetic Inhibitors against CDC7
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DOI：
10.1002/minf.201800022
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发表时间：
2018-07
影响因子：
3.6
通讯作者：
F. R. Makhouri;Jahan B. Ghasemi
中科院分区：
文献类型：
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作者：
F. R. Makhouri;Jahan B. Ghasemi
利用小分子抑制蛋白质-蛋白质相互作用(PPI)，干扰这些复合体的形成，调节关键的调控途径，具有治疗意义。DBF4依赖的激酶CDC7是S阶段的检查点通路靶标，在多种生物对DNA损伤和复制应激的正确反应中发挥着重要作用。CDC7及其蛋白调节因子DBF4的过度表达具有高度的神经毒性，并促进癌症和神经退行性变。在本研究中，我们模拟DBF4的药效特性进行了虚拟筛选，并通过高通量对接和分子动力学模拟评估了它们对CDC7的潜在抑制活性。计算确定了五个小分子对CDC7蛋白的活性部位区域表现出高亲和力。
Inhibition protein‐protein interactions (PPIs) using small molecules, that interfere with the formation of these complexes, modulates critical regulatory pathways and has therapeutic significance. DBF4‐dependent kinase CDC7 is the S‐phase checkpoint pathway target, which plays an important role for a proper response to DNA damage and replicative stress in multiple organisms. Overexpression of CDC7 and its protein regulator DBF4 is highly neurotoxic and promotes cancer and neurodegeneration. In the present study, virtual screening of inhibitor scaffolds mimicking DBF4 pharmacophoric properties was carried out and evaluation of their potential inhibitory activity toward CDC7 was performed using high‐throughput docking and molecular dynamics simulations. The calculations identified five small molecules exhibiting a high affinity to the active site region of the CDC7 protein.