Kumar Abhishek, Bharadwaj Tharun, Muthuraj Likith, Kumar Jitendra, Kumar Pravin, Lalitha Roopa, Sigamani Gladstone, Ahmad Shaban, Bhanu Piyush, Pathak Ravi Kant, Uttarkar Akshay, Niranjan Vidya, Mishra Vachaspati
Department of Computational Biology and AI, Kcat Enzymatic Private Limited, #16, Ramakrishnappa Road, Cox Town, Bangalore, 560005, India.
Biotechnology Industry Research Assistance Council (BIRAC), NSIC Business Park, NSIC Bhawan, Okhla Industrial Estate, New Delhi, 110020, India.
Sci Rep. 2025 Apr 30;15(1):15225. doi: 10.1038/s41598-024-78411-5.
Nuclear factor-kappa B (NF-kB) plays a crucial role in numerous cellular processes, such as inflammation, immunological responses to infection, cell division, apoptosis, and the development of embryos and neurons. Cytokines, plays an important role in positive feedback loop and leads to inflammatory cell death through the release of pathogenic cytokine known to be cytokine storm which causes diseases like Acute Respiratory Disorder (ARD), multi-organ disorder, Hyperinflammation syndrome and may cause death. This cytochrome storm was identified in the people severely affected by covid-19. NF-kB presents a promising therapeutic opportunity to mitigate covid-19-induced cytokine storm and reduce the risk of severe morbidity and mortality resulting from the diseases. This paper therefore explores the modulation of the NF-kB pathway by inhibiting the binding of the transcription factor as a potential strategy to mitigate the morbidity and mortality caused by cytokine storms. To identify small molecule inhibitors of NF-kB signaling, we screened approximately 101 molecules in two identified pockets of NF-kB (p50/p65)-DNA complex. Each molecule was virtually screened in two pockets (A1 and A2). The focus library was developed starting from chemical structures obtained from the literature (Angelicin and Psolaren) which shows the inhibition of NF-kB signaling, as well as using artificial intelligence (WADDAICA) and rationally designed molecules. Among the 3 highest-scored ligands (NFAI64, NF30 and NF49) selected from the docking studies and further molecular dynamic investigations. The identified compound NF30 showed significantly higher binding affinity (ΔG) in A2 pocket (60.92 ± 1.83 kJ/mol) as compared to the rest of the molecules, making it a promising molecule for the inhibition of NF-kB. The discovered novel compounds by computational studies could be of relevance to identify more potent inhibitors of NF-kB dependent biological functions beneficial to control the cytokine storm occurring in the patients affected with Covid-19.
核因子-κB（NF-κB）在众多细胞过程中发挥着关键作用，如炎症、对感染的免疫反应、细胞分裂、细胞凋亡以及胚胎和神经元的发育。细胞因子在正反馈回路中起重要作用，并通过释放已知为细胞因子风暴的致病性细胞因子导致炎症细胞死亡，细胞因子风暴会引发急性呼吸障碍（ARD）、多器官障碍、过度炎症综合征等疾病，甚至可能导致死亡。这种细胞因子风暴在受新冠病毒-19严重影响的人群中被发现。NF-κB为减轻新冠病毒-19诱导的细胞因子风暴以及降低该疾病导致的严重发病和死亡风险提供了一个有前景的治疗机会。因此，本文探讨了通过抑制转录因子的结合来调节NF-κB途径，作为减轻细胞因子风暴所致发病和死亡的潜在策略。为了鉴定NF-κB信号传导的小分子抑制剂，我们在NF-κB（p50/p65）-DNA复合物的两个已确定口袋中筛选了约101种分子。每个分子都在两个口袋（A1和A2）中进行虚拟筛选。聚焦文库是从文献中获得的化学结构（当归素和补骨脂素）开始构建的，这些结构显示出对NF-κB信号传导的抑制作用，同时还使用了人工智能（WADDAICA）和合理设计的分子。在对接研究和进一步的分子动力学研究中选出的3个得分最高的配体（NFAI64、NF30和NF49）中。与其他分子相比，鉴定出 的化合物NF30在A2口袋中显示出显著更高的结合亲和力（ΔG）（60.92±1.83 kJ/mol），使其成为一种有前景的抑制NF-κB的分子。通过计算研究发现的新型化合物可能有助于鉴定更有效的NF-κB依赖性生物学功能抑制剂，从而有利于控制新冠病毒-19感染患者中发生的细胞因子风暴。
