Singh Nilay, Sharma Promila, Pal Manoj K, Kahera Ragini, Badoni Himani, Pant Kumud, Sharma Neetu, Bhist Bhawana
Department of Biotechnology, Graphic Era (Deemed to be University), 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India.
Department of Microbiology, Graphic Era (Deemed to be University), 566/6 Bell Road, Clement Town, Dehradun, Uttarakhand, India.
Sci Rep. 2025 May 14;15(1):16677. doi: 10.1038/s41598-024-79054-2.
The NLRP3 inflammasome plays a pivotal role in the innate immune system, orchestrating the activation of caspase-1 and the release of proinflammatory cytokines IL-1β and IL-18 in reaction to microbial infections and cellular damage. Despite its crucial function in defending against pathogens, the dysregulated activation of the NLRP3 inflammasome has been associated with various inflammatory disorders. In the current investigation, promising plant-derived alkaloids compounds have been discovered as targeted inhibitors against multiprotein NLRP3 using an in-silico drug development approach. The repurposing of natural compounds as anti-inflammatory agents remains a relevant approach for identifying promising early interventions to prevent and manage inflammatory diseases. In this molecular docking study targeting Chain A of the NLRP3 inflammasome protein, eight plant-derived alkaloids renowned for their anti-inflammatory properties were chosen. Docking analysis of the selected alkaloids showed the lowest/best binding energies of less than - 10 Kcal/mol against NLRP3 Chain A, based on this docking result, which is regarded as an exceptional binding score. Notably, Oxyacanthine, Magnoflorine, Corynoline, and Berbamine demonstrated the most favourable binding energies, displaying unique interactions within the binding pocket of the NACHT/PYD domain of NLRP3 Chain A among all compounds investigated. These findings highlight the potential of these alkaloids as promising therapeutic candidates specifically targeting this trans-activating NACHT/PYD domain of NLRP3 Chain A in the context of anti-inflammatory interventions. Protein-protein interactions (PPIs) play an important role in elucidating protein function and drug interactions. To identify bioactive compounds with anti-inflammatory potential, a functional protein network was constructed from publicly available PPI data. As a result, the findings of this in-silico study may cause researchers to emphasize more on alkaloids when considering natural plant products for the treatment of various illnesses that target the inflammatory intermediates. This computational approach predicted ligands that may modulate inflammatory proteins and support host immunity. However, further in vitro and in vivo studies are still needed to validate these in-silico findings before clinical use. In summary, analysing PPI networks can aid discovery of therapeutic candidates, but experimental validation remains essential.
NLRP3炎性小体在先天免疫系统中起关键作用，在对微生物感染和细胞损伤的反应中，协调半胱天冬酶-1的激活以及促炎细胞因子IL-1β和IL-18的释放。尽管其在抵御病原体方面具有关键功能，但NLRP3炎性小体的失调激活与多种炎症性疾病有关。在当前的研究中，使用计算机辅助药物开发方法发现了有前景的植物源生物碱化合物作为针对多蛋白NLRP3的靶向抑制剂。将天然化合物重新用作抗炎剂仍然是确定有前景的早期干预措施以预防和管理炎症性疾病的一种相关方法。在这项针对NLRP3炎性小体蛋白A链的分子对接研究中，选择了八种以其抗炎特性而闻名的植物源生物碱。所选生物碱的对接分析显示，基于该对接结果，其与NLRP3 A链的最低/最佳结合能小于-10千卡/摩尔，这被视为优异的结合分数。值得注意的是，在所有研究的化合物中，氧化刺桐碱、木兰碱、紫堇灵和小檗胺表现出最有利的结合能，在NLRP3 A链的NACHT/PYD结构域的结合口袋内显示出独特的相互作用。这些发现突出了这些生物碱作为有前景的治疗候选物的潜力，特别是在抗炎干预的背景下靶向NLRP3 A链的这种反式激活NACHT/PYD结构域。蛋白质-蛋白质相互作用（PPI）在阐明蛋白质功能和药物相互作用中起重要作用。为了鉴定具有抗炎潜力的生物活性化合物，从公开可用的PPI数据构建了一个功能性蛋白质网络。结果，这项计算机辅助研究的发现可能会使研究人员在考虑将天然植物产品用于治疗针对炎症中间体的各种疾病时，更多地强调生物碱。这种计算方法预测了可能调节炎症蛋白并支持宿主免疫的配体。然而，在临床使用之前，仍需要进一步的体外和体内研究来验证这些计算机辅助研究的结果。总之，分析PPI网络有助于发现治疗候选物，但实验验证仍然至关重要。
