PDF(Pubmed)
Abstract：
Therapeutic targeting of Sp1 transcription factor and survivin, are studied in various cancers due to their consistent overexpression. These markers result in poorer cancer prognoses and their downregulation has been investigated as an effective treatment approach. Mithramycin-A and Tolfenamic acid are two drugs with innate anti-cancer properties and are suggested to be able to target Sp1 through GC/GT DNA binding interference, however in-depth binding and mechanistic studies are lacking. Through docking analysis, we investigated Mithramycin-A and Tolfenamic acid in terms of their specific binding interactions with Sp1 and survivin. Through further molecular dynamics simulations including Root Mean Square (RMS) Fluctuation and RMS Deviation, rGYr, and H-bond analysis, we identified critical residues involved in drug interactions with each protein in question. We show Mithramycin-A as the superior binding candidate to each protein and found that it exhibited stronger binding with Sp1, and then survivin. Subsequent molecular dynamics simulations followed the same trend as initial binding energy calculations and showed crucial amino acids involved in each Mithramycin-A-protein complex. Our findings warrant further investigation into Mithramycin-A and its specific interaction with Sp1 and their downstream targets giving a better understanding of Mithramycin-A and its potential as an effective cancer treatment.
摘要：
Sp1转录因子和survivin的靶向治疗,由于它们一致的过表达，在各种癌症中进行了研究。这些标记物导致较差的癌症预后,并且它们的下调已经作为有效的治疗方法被研究。米霉素A和托芬那酸是两种具有固有抗癌特性的药物，被认为能够通过GC/GTDNA结合干扰靶向Sp1，然而，缺乏深入的结合和机理研究。通过对接分析,我们研究了米霉素A和托芬那酸与Sp1和survivin的特异性结合相互作用.通过进一步的分子动力学模拟，包括均方根（RMS）波动和RMS偏差，rGYr,和H键分析，我们确定了涉及药物与每种蛋白质相互作用的关键残基.我们显示了米霉素-A作为每种蛋白质的优异结合候选物，并发现它表现出与Sp1和survivin的更强结合。随后的分子动力学模拟遵循与初始结合能计算相同的趋势，并显示了每种米霉素-A蛋白复合物中涉及的关键氨基酸。我们的发现值得进一步研究米霉素A及其与Sp1及其下游靶标的特异性相互作用，从而更好地了解米霉素A及其作为有效癌症治疗的潜力。
