Nasti Rita, Rossi Daniela, Amadio Marialaura, Pascale Alessia, Unver M Yagiz, Hirsch Anna K H, Collina Simona
Department of Drug Sciences, Medicinal Chemistry and Technology Section, University of Pavia , Via Taramelli 12, 27100 Pavia, Italy.
Department of Drug Sciences, Pharmacology Section, University of Pavia , Via Taramelli 14, 27100 Pavia, Italy.
J Med Chem. 2017 Oct 26;60(20):8257-8267. doi: 10.1021/acs.jmedchem.6b01871. Epub 2017 Jun 19.
RNA-binding proteins play a key role in post-transcriptional processes. Among these proteins, embryonic lethal abnormal vision (ELAV) proteins are among the best described. ELAV proteins predominantly act as positive regulators of gene expression, and their dysregulation is involved in several pathologies, such as cancer, inflammation, and neurodegenerative diseases. Only a few structurally unrelated compounds interfering with ELAV protein-mRNA complexes have been identified by applying high-throughput screening approaches. Considering the structural diversity of the compounds discovered so far and the different techniques employed for screening their ability to interfere with ELAV protein-mRNA complexes, drawing conclusions from structure-activity relationships remains a challenge. We performed docking studies to understand the interactions of compounds reported over the past decade to be inhibitors of ELAV proteins and to evaluate the potential of computer-aided drug design to target this family of proteins for further drug discovery.
RNA结合蛋白在转录后过程中发挥关键作用。在这些蛋白中,胚胎致死异常视觉(ELAV)蛋白是研究得最为透彻的蛋白之一。ELAV蛋白主要作为基因表达的正向调节因子,其失调与多种病理状况有关,如癌症、炎症和神经退行性疾病。通过高通量筛选方法,仅鉴定出了少数几种结构不相关的化合物可干扰ELAV蛋白-mRNA复合物。鉴于目前发现的化合物的结构多样性以及用于筛选其干扰ELAV蛋白-mRNA复合物能力的不同技术,从构效关系得出结论仍然是一项挑战。我们进行了对接研究,以了解过去十年报道的作为ELAV蛋白抑制剂的化合物的相互作用,并评估计算机辅助药物设计针对该蛋白家族进行进一步药物发现的潜力。