Abstract：
Lupus Nephritis (LN) is an autoimmune disease affecting the kidneys, and conventional drug studies have limitations due to its imprecise and complex pathogenesis. Therefore, the aim of this study was to design a novel Lupus Nephritis-targeted drug with good clinical due potential, high potency and selectivity by computer-assisted approach.NIK belongs to the serine/threonine protein kinase, which is gaining attention as a drug target for Lupus Nephritis. we used bioinformatics, homology modelling and sequence comparison analysis, small molecule ab initio design, ADMET analysis, molecular docking, molecular dynamics simulation, and MM/PBSA analysis to design and explore the selectivity and efficiency of a novel Lupus Nephritis-targeting drug, ClImYnib, and a classical NIK inhibitor, NIK SMI1. We used bioinformatics techniques to determine the correlation between lupus nephritis and the NF-κB signaling pathway. De novo drugs design was used to create a NIK-targeted inhibitor, ClImYnib, with lower toxicity, after which we used molecular dynamics to simulate NIK SMI1 against ClImYnib, and the simulation results showed that ClImYnib had better selectivity and efficiency. Our research delves into the molecular mechanism of protein ligands, and we have designed and validated an excellent NIK inhibitor using multiple computational simulation methods. More importantly, it provides an idea of target designing small molecules.Communicated by Ramaswamy H. Sarma.
摘要：
狼疮性肾炎（LN）是一种影响肾脏的自身免疫性疾病，和常规药物研究由于其不精确和复杂的发病机制而存在局限性。因此,这项研究的目的是设计一种新型的狼疮性肾炎靶向药物，具有良好的临床疗效，通过计算机辅助方法实现高效能和选择性。NIK属于丝氨酸/苏氨酸蛋白激酶，作为狼疮性肾炎的药物靶点正在引起人们的注意。我们使用了生物信息学，同源性建模和序列比较分析，小分子从头设计，ADMET分析,分子对接,分子动力学模拟,和MM/PBSA分析设计并探索新型狼疮性肾炎靶向药物的选择性和有效性,克莱姆尼布,和经典的NIK抑制剂，NIKSMI1。我们使用生物信息学技术来确定狼疮性肾炎与NF-κB信号通路之间的相关性。从头药物设计用于创建NIK靶向抑制剂，克莱姆尼布,毒性较低，之后，我们使用分子动力学模拟NIKSMI1对抗ClImYnib，模拟结果表明ClImYnib具有较好的选择性和效率。我们的研究深入到蛋白质配体的分子机制,我们使用多种计算模拟方法设计并验证了一种优秀的NIK抑制剂。更重要的是,它提供了一种设计小分子目标的思路。由RamaswamyH.Sarma沟通。
