Exploring New Potential Pkcθ Inhibitors Using Pharmacophore Modeling, Molecular Docking Analysis, and Molecular Dynamics Simulations

IF 1.2 4区 医学 Q4 CHEMISTRY, MEDICINAL
Yao Yao, Wen-Wei Pang, An-Zheng Hu, Hai-Yan Chen, Zhong-Quan Qi
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Abstract

Background: It has been reported that PKCθ plays an important role in the immune response by regulating the cellular activity of T cells and, thus, the production of immune factors such as IL-2.PKCθ protein is mainly expressed in T lymphocytes but not much in other cells and has a very good specificity. Therefore, it is very meaningful to use PKCθ protein as a novel target for immunosuppression. PKCθ is a valuable target that can be used to develop meaningful novel selective immunosuppressive agents. Methods: In this study, we constructed a 3-characteristic pharmacophore(RHA)and used it to perform a virtual screening of the database. Then, we performed a molecular docking analysis of the compounds that scored high. The top five compounds with molecular docking scores were used as lead compounds, and structure-based ligand design via fragment substitution was applied to them, resulting in 20077 new compounds. We performed molecular docking analysis, binding free energy calculations, molecular dynamics simulation, and ADMET prediction on these new compounds and finally identified two compounds as new PKCθ inhibitors. Results and Discussions: Through the screening of pharmacophore, molecular design based on fragment substitution, molecular docking, we finally obtained two small molecules with higher scores than the positive control, in which the molecular docking score of P01 was -53.88 kcal/mol, and the molecular docking score of P02 was -51.20 kcal/mol, and then we performed the molecular dynamics simulation, free energy of binding calculations, and the prediction of ADMET properties for the compounds. The results showed that the ligands could form more stable complexes with the proteins, the binding free energy calculations of the ligand molecules were better than the positive control, all of them had good ADMET properties, and the compounds all had good drug similarity. Conclusion: Our results provided 2 new ligands that could serve as lead compounds for new PKCθ inhibitors in the future.
利用药效学建模、分子对接分析和分子动力学模拟探索新的潜在 Pkcθ 抑制剂
背景:据报道,PKCθ通过调节T细胞的细胞活性,进而调节IL-2等免疫因子的产生,在免疫反应中发挥着重要作用。因此,将 PKCθ 蛋白作为免疫抑制的新靶点是非常有意义的。PKCθ 是一个有价值的靶点,可用于开发有意义的新型选择性免疫抑制剂。方法:在这项研究中,我们构建了一个3特征药代结构(RHA),并利用它对数据库进行了虚拟筛选。然后,我们对得分较高的化合物进行了分子对接分析。将分子对接得分最高的五个化合物作为先导化合物,通过片段置换进行基于结构的配体设计,最终得到了20077个新化合物。我们对这些新化合物进行了分子对接分析、结合自由能计算、分子动力学模拟和 ADMET 预测,最终确定了两个化合物为新的 PKCθ 抑制剂。结果与讨论通过药效学筛选、基于片段置换的分子设计、分子对接,我们最终得到了两个得分高于阳性对照的小分子化合物,其中P01的分子对接得分为-53.88 kcal/mol,P02的分子对接得分为-51.20 kcal/mol,然后对化合物进行了分子动力学模拟、结合自由能计算和ADMET性质预测。结果表明,配体能与蛋白质形成较稳定的复合物,配体分子的结合自由能计算结果优于阳性对照,所有配体均具有良好的 ADMET 特性,化合物均具有良好的药物相似性。结论我们的研究结果提供了两种新的配体,可作为未来新的 PKCθ 抑制剂的先导化合物。
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来源期刊
CiteScore
1.80
自引率
10.00%
发文量
245
审稿时长
3 months
期刊介绍: Aims & Scope Letters in Drug Design & Discovery publishes letters, mini-reviews, highlights and guest edited thematic issues in all areas of rational drug design and discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, and structure-activity relationships. The emphasis is on publishing quality papers very rapidly by taking full advantage of latest Internet technology for both submission and review of manuscripts. The online journal is an essential reading to all pharmaceutical scientists involved in research in drug design and discovery.
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