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Screening approaches against claudin-4 focusing on therapeutics through molecular docking and the analysis of their relative dynamics: a theoretical approach
Journal of Receptors and Signal Transduction ( IF 2.8 ) Pub Date : 2020-04-22 , DOI: 10.1080/10799893.2020.1752717
Majji Rambabu 1 , Sivaraman Jayanthi 1
Affiliation  

Abstract Claudin-4 (CLDN4) is a class of transmembrane protein in the family of tight junction (TJ) proteins. Overexpression of CLDN4 is reported in the case of ovarian cancer and epithelial malignancies. The current study is focused on the identification of lead compounds for CLDN4 adopting the structure-based drug design method. The Schrodinger glide is used as a molecular docking tool for the initial docking of CLDN4 with Asinex Database by performing high throughput virtual screening, top hits were identified. Then, compounds BDF 33196188 and BDE 30874918 were identified by molecular docking based on binding energy in the active site of CLDN4. Subsequently, critical residues were identified such as Asp146 and Arg158 with the least binding energy from Extra Precision method. Further, molecular dynamics simulations of claudin-4 protein were used for the optimization of best ligands with claudin-4 in a dynamic system. Molecular docking and molecular dynamics simulations predicted critically important residues ASP146 and ARG158 involved in claudin-4 binding. The hits retrieved from screening were docked into protein by relevant procedures including HTVS, SP, and XP. Finally, two molecules were identified as potential claudin-4 inhibitors. The two ligands BDF 33196188 and BDE 30874918 are suggested as potential inhibitors for CLDN4. In summary, our computational strategy established novel leads against CLDN4 from Asinex Database and recommended as anti-cancer agents.

中文翻译:

通过分子对接筛选针对claudin-4的治疗方法及其相对动力学分析:一种理论方法

摘要 Claudin-4(CLDN4)是紧密连接(TJ)蛋白家族中的一类跨膜蛋白。在卵巢癌和上皮恶性肿瘤的情况下报道了 CLDN4 的过度表达。目前的研究重点是采用基于结构的药物设计方法鉴定 CLDN4 的先导化合物。Schrodinger glide 用作分子对接工具,用于通过执行高通量虚拟筛选将 CLDN4 与 Asinex 数据库进行初始对接,确定了最高命中。然后,基于 CLDN4 活性位点的结合能,通过分子对接鉴定了化合物 BDF 33196188 和 BDE 30874918。随后,从超精密方法中鉴定出结合能最低的关键残基,例如 Asp146 和 Arg158。更多,claudin-4 蛋白的分子动力学模拟用于在动态系统中优化具有 claudin-4 的最佳配体。分子对接和分子动力学模拟预测了参与 claudin-4 结合的至关重要的残基 ASP146 和 ARG158。通过HTVS、SP和XP等相关程序将筛选中检索到的命中物对接到蛋白质中。最后,两个分子被确定为潜在的 claudin-4 抑制剂。两种配体 BDF 33196188 和 BDE 30874918 被认为是 CLDN4 的潜在抑制剂。总之,我们的计算策略从 Asinex 数据库中建立了针对 CLDN4 的新线索,并被推荐为抗癌药物。分子对接和分子动力学模拟预测了参与 claudin-4 结合的至关重要的残基 ASP146 和 ARG158。通过HTVS、SP和XP等相关程序将筛选中检索到的命中物对接到蛋白质中。最后,两个分子被确定为潜在的 claudin-4 抑制剂。两种配体 BDF 33196188 和 BDE 30874918 被认为是 CLDN4 的潜在抑制剂。总之,我们的计算策略从 Asinex 数据库中建立了针对 CLDN4 的新线索,并被推荐为抗癌药物。分子对接和分子动力学模拟预测了参与 claudin-4 结合的至关重要的残基 ASP146 和 ARG158。通过HTVS、SP和XP等相关程序将筛选中检索到的命中物对接到蛋白质中。最后,两个分子被确定为潜在的 claudin-4 抑制剂。两种配体 BDF 33196188 和 BDE 30874918 被认为是 CLDN4 的潜在抑制剂。总之,我们的计算策略从 Asinex 数据库中建立了针对 CLDN4 的新线索,并被推荐为抗癌药物。两种配体 BDF 33196188 和 BDE 30874918 被认为是 CLDN4 的潜在抑制剂。总之,我们的计算策略从 Asinex 数据库中建立了针对 CLDN4 的新线索,并被推荐为抗癌药物。两种配体 BDF 33196188 和 BDE 30874918 被认为是 CLDN4 的潜在抑制剂。总之,我们的计算策略从 Asinex 数据库中建立了针对 CLDN4 的新线索,并被推荐为抗癌药物。
更新日期:2020-04-22
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