<i>In silico</i> screening of phytoconstituents as potential anti-inflammatory agents targeting NF-κB p65: an approach to promote burn wound healing

Chronic burn wounds are frequently characterised by a prolonged and dysregulated inflammatory phase that is mediated by over-activation of NF-κB p65. Synthetic wound healing drugs used for treatment of inflammation are primarily associated with several shortcomings which reduce their therapeutic index. In this scenario, phytoconstituents that exhibit multifaceted biological activities including anti-inflammatory effects have emerged as a promising therapeutic alternative. However, identification and isolation of phytoconstituents from medicinal herbs is a cumbersome method that is linked to profound uncertainty. Hence, present study aimed to identify prospective phytoconstituents as inhibitors of RHD of NF-κB p65 by utilizing <i>in silico</i> approach. Virtual screening of 2821 phytoconstituents was performed against protein model. Out of 2821 phytoconstituents, 162 phytoconstituents displayed a higher binding affinity (≤ −8.0 kcal/mol). These 162 phytoconstituents were subjected to ADMET predictions, and 15 of them were found to satisfy Lipinski’s rule of five and showed favorable pharmacokinetic properties. Among these 15 phytoconstituents, 5 phytoconstituents with high docking scores i.e. silibinin, bismurrayaquinone A, withafastuosin B, yuccagenin, (+)-catechin 3-gallate were selected for molecular dynamics (MD) simulation analysis. Results of MD simulation indicated that withafastuosin B, (+)-catechin 3-gallate and yuccagenin produced a compact and stable complex with protein without significant variations in conformation. Relative binding energy analysis of best hit molecules indicate that withafastuosin B, and (+)-catechin 3-gallate exhibit high binding affinity with target protein among other lead molecules. Findings of study suggest that these phytoconstituents could serve as promising anti-inflammatory agents for treatment of burn wounds by inhibiting the RHD of NF-κB p65.慢性烧伤创面常以持续失调的炎症阶段为特征，该阶段由核因子κB p65（NF-κB p65）的过度活化所介导。当前用于炎症治疗的合成创面愈合药物往往存在多种缺陷，会降低其治疗指数。在此背景下，具备包括抗炎作用在内的多方面生物活性的植物活性成分，已成为极具潜力的治疗替代方案。然而，从药用植物中鉴定并分离植物活性成分是一项繁琐的工作，且伴随较高的不确定性。因此，本研究旨在通过计算机模拟（in silico）方法，筛选可抑制核因子κB p65的Rel同源结构域（RHD）的潜在植物活性成分。本研究针对靶蛋白模型对2821种植物活性成分开展了虚拟筛选。在2821种植物活性成分中，有162种表现出较高的结合亲和力（≤−8.0 kcal/mol）。随后对这162种成分进行ADMET（吸收、分布、代谢、排泄、毒性）预测，其中15种符合Lipinski五规则，并展现出良好的药代动力学性质。在这15种成分中，选取5种对接得分较高的化合物，即水飞蓟宾（silibinin）、双穆里雅醌A（bismurrayaquinone A）、睡茄辛B（withafastuosin B）、丝兰皂苷元（yuccagenin）以及(+)-儿茶素没食子酸酯[(+)-catechin 3-gallate]，进行分子动力学（MD）模拟分析。分子动力学模拟结果显示，睡茄辛B、(+)-儿茶素没食子酸酯与丝兰皂苷元可与靶蛋白形成紧凑稳定的复合物，其构象未出现显著变化。对最佳命中分子的相对结合能分析表明，相较于其他先导分子，睡茄辛B与(+)-儿茶素没食子酸酯与靶蛋白的结合亲和力更高。本研究结果提示，这些植物活性成分可通过抑制核因子κB p65的Rel同源结构域，成为治疗烧伤创面的极具前景的抗炎制剂。

搜集汇总

背景与挑战

背景概述

该数据集支持一项利用计算机模拟筛选植物成分作为抗炎剂的研究，旨在通过抑制NF-κB p65促进烧伤伤口愈合。研究对2821种植物成分进行虚拟筛选，结合ADMET预测和分子动力学模拟，最终识别出withafastuosin B和(+)-catechin 3-gallate等有前景的成分，数据集包含相关原始数据文件，适用于生物物理学、药理学等领域分析。