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首页> 外文期刊>Journal of Pharmacology and Pharmacotherapeutics >Virtual screening studies reveal linarin as a potential natural inhibitor targeting CDK4 in retinoblastoma
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Virtual screening studies reveal linarin as a potential natural inhibitor targeting CDK4 in retinoblastoma

机译：虚拟筛选研究显示藤黄素是视网膜母细胞瘤中潜在的靶向CDK4的天然抑制剂

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Objective:To find out whether linarin can be used as a potential natural inhibitor to target CDK4 in retinoblastoma using virtual screening studies.Materials and Methods:In this study, molecular modeling and protein structure optimization was performed for crystal structure of CDK4 (PDB id: 3G33), and was subjected to Molecular Dynamics (MD) simulation for 10 nanoseconds, as a preparatory process for docking. Furthermore, the stable conformation obtained in the MD simulation was utilized for virtual screening against the library of natural compounds in Indian Plant Anticancer Compounds Database (InPACdb) using AutoDock Vina. Finally, best docked ligands were revalidated individually through semi-flexible docking by AutoDock 4.0.Results:The CDK4 structure was stereochemically optimized to fix clashes and bad angles, which placed 96.4% residues in the core region of Ramachandran plot. The final structure of CDK4 that emerged after MD simulation was proven to be highly stable as per different validation tools. Virtual screening and docking was carried out for CDK4 against optimized ligands from InPACdb through AutoDock Vina. This inferred Linarin (Inpacdb AC.NO. acd0073) as a potential therapeutic agent with binding energy of -8.9 kJ/mol. Furthermore, it was also found to be valid as per AutoDock 4.0 semi-flexible docking procedure, with the binding energy of -8.18 kJ/mol and Ki value of 1.01 μM.Conclusion:The docking results indicate linarin, a flavonoid plant compound, as a potential inhibitor of CDK4 compared to some of the currently practiced anticancer drugs for retinoblastoma. This finding can be extended to experimental validation to assess the in vivo efficacy of the identified compound.
机译：目的：通过虚拟筛选研究来确定藤黄素是否可以用作视网膜母细胞瘤中靶向CDK4的潜在天然抑制剂。材料与方法：在这项研究中，对CDK4的晶体结构进行了分子建模和蛋白质结构优化（PDB id： 3G33），并进行了10纳秒的分子动力学（MD）模拟，作为对接的准备过程。此外，在MD模拟中获得的稳定构象用于使用AutoDock Vina对印度植物抗癌化合物数据库（InPACdb）中的天然化合物库进行虚拟筛选。最后，最好的对接配体通过AutoDock 4.0的半柔性对接分别进行重新验证。结果：对CDK4结构进行了立体化学优化，以修复碰撞和不良角度，其中96.4％的残基位于Ramachandran图的核心区域。根据不同的验证工具，MD模拟后出现的CDK4最终结构被证明是高度稳定的。针对来自InPACdb的优化配体通过AutoDock Vina对CDK4进行了虚拟筛选和对接。这推断利纳林（Inpacdb AC.NO. acd0073）是一种潜在的治疗剂，其结合能为-8.9 kJ / mol。此外，根据AutoDock 4.0半挠性对接程序也发现它是有效的，其结合能为-8.18 kJ / mol，Ki值为1.01μM。结论：对接结果表明类黄酮植物化合物亚麻苦素为与目前针对视网膜母细胞瘤的某些抗癌药物相比，CDK4是一种潜在的CDK4抑制剂。该发现可以扩展到实验验证，以评估所鉴定化合物的体内功效。

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