乳腺癌(BC)在世界范围内普遍存在,是女性死亡的主要原因。然而,细胞表面葡萄糖调节蛋白78(cs-GRP78)在几种类型的癌症和病原体感染中过表达。这项研究检查了FDA批准的两种著名的BC药物作为GRP78的BC治疗方法。第一种类型包括基于细胞周期蛋白的激酶4/6的抑制剂,包括abemaciclib,palbociclib,ribociclib,和dinaciclib。此外,衣霉素,和阿霉素,这是早期和晚期BC最有效的抗癌药物之一,对GRP78进行了测试。由于(-)-表半乳糖儿茶素没食子酸酯抑制GRP78,其也被评估(用作阳性对照)。因此,使用分子动力学模拟方法,这项研究旨在研究靶向GRP78的优势,GRP78代表了一种有希望的癌症治疗方案.鉴于计算药物反应预测模型的最新进展,这项研究旨在检查GRP78靶向的益处,这代表了一种有前途的癌症治疗方案,利用分子对接和分子动力学模拟相结合的方法。模拟蛋白质(50ns)与药物对接,然后进行了100ns的第二轮动力学模拟。之后,在模拟期间,每个络合物的结合自由能从30到100ns计算。这些发现证明了abemaciclib的疗效,ribociclib,和衣霉素与GRP78的核苷酸结合域结合,为阐明这些药物与过表达GRP78的癌症(和其他应激)细胞之间的相互作用模式铺平了道路。由RamaswamyH.Sarma沟通。
Breast cancer (BC) is prevalent worldwide and is a leading cause of death among women. However, cell-surface glucose-regulated protein 78 (cs-
GRP78) is overexpressed in several types of cancer and during pathogen infections. This
study examines two well-known BC drugs approved by the FDA as BC treatments to
GRP78. The first type consists of inhibitors of cyclin-based kinases 4/6, including abemaciclib, palbociclib, ribociclib, and dinaciclib. In addition, tunicamycin, and doxorubicin, which are among the most effective anticancer drugs for early and late-stage BC, are tested against GRP78. As (-)-epiGallocatechin gallate inhibits GRP78, it is also being evaluated (used as positive control). Thus, using molecular dynamics simulation approaches, this
study aims to examine the advantages of targeting
GRP78, which represents a promising cancer therapy regime. In light of recent advances in computational drug response prediction models, this
study aimed to examine the benefits of GRP78 targeting, which represents a promising cancer therapy regime, by utilizing combined molecular docking and molecular dynamics simulation approaches. The simulated protein (50 ns) was docked with the drugs, then a second round of dynamics simulation was performed for 100 ns. After that, the binding free energies were calculated from 30 to 100 ns for each complex during the simulation period. These findings demonstrate the efficacy of abemaciclib, ribociclib, and tunicamycin in binding to the nucleotide-binding domain of the GRP78, paving the way for elucidating the mode of interactions between these drugs and cancer (and other stressed) cells that overexpress GRP78.Communicated by Ramaswamy H. Sarma.