Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box. 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
Sci Rep. 2020 Dec 1;10(1):20974. doi: 10.1038/s41598-020-77750-3.
Tumor Necrosis Factor Alpha (TNF-α) is a pleiotropic pro-inflammatory cytokine. It act as central biological regulator in critical immune functions, but its dysregulation has been linked with a number of diseases. Inhibition of TNF-α has considerable therapeutic potential for diseases such as cancer, diabetes, and especially autoimmune diseases. Despite the fact that many small molecule inhibitors have been identified against TNF-α, no orally active drug has been reported yet which demand an urgent need of a small molecule drug against TNF-α. This study focuses on the development of ligand-based selective pharmacophore model to perform virtual screening of plant origin natural product database for the identification of potential inhibitors against TNF-α. The resultant hits, identified as actives were evaluated by molecular docking studies to get insight into their potential binding interaction with the target protein. Based on pharmacophore matching, interacting residues, docking score, more affinity towards TNF-α with diverse scaffolds five compounds were selected for in vitro activity study. Experimental validation led to the identification of three chemically diverse potential compounds with the IC 32.5 ± 4.5 µM, 6.5 ± 0.8 µM and 27.4 ± 1.7 µM, respectively.
肿瘤坏死因子-α（TNF-α）是一种多功能促炎细胞因子。它作为关键免疫功能的中央生物调节剂发挥作用，但它的失调与许多疾病有关。TNF-α 的抑制作用对癌症、糖尿病，特别是自身免疫性疾病具有相当大的治疗潜力。尽管已经鉴定出许多针对 TNF-α 的小分子抑制剂，但目前尚未报道具有口服活性的药物，因此迫切需要针对 TNF-α 的小分子药物。本研究专注于基于配体的选择性药效团模型的开发，以对植物源天然产物数据库进行虚拟筛选，寻找潜在的 TNF-α 抑制剂。鉴定出的命中化合物被评估为活性化合物，通过分子对接研究来深入了解它们与靶蛋白的潜在结合相互作用。基于药效团匹配、相互作用残基、对接得分、对 TNF-α 的更高亲和力以及不同骨架，选择了五种化合物进行体外活性研究。实验验证导致鉴定出三种具有化学多样性的潜在化合物，其 IC 32.5 ± 4.5 μM、6.5 ± 0.8 μM 和 27.4 ± 1.7 μM。
