B‐Raf kinase is a vital intermedium in the mitogen‐activated protein kinase (MAPK) signaling pathway, which transforms extracellular signals into cellular mechanisms. Mutations in this kinase, for instance, the most common V600E mutation, can lead to the ERK signaling pathologically activated and hence cause severe diseases such as somatic tumors. So far, the development of B‐Raf inhibitors has made remarkable progress. However, the resistance and relapse of approved Raf drugs have been widely reported, and the optimization for old drugs and the discovery for new inhibitors still remain a significant task. In this study, we designed and evaluated a series of novel B‐Raf^V600E inhibitors. A fragment library has been established before the docking simulation carried out using the MCSS strategy (multicopy simulation search). The appropriate fragments were reassembled to provide new candidate compounds, which were further screened by iterative docking simulations and molecular dynamics. Bioassays were carried out to evaluate the pharmacological profile of the compounds identified and synthesized. The result showed that compound 5n had an impressive enzyme inhibitory and antiproliferation activity, suggesting a promising potential in the future study.

中文翻译：

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通过多拷贝模拟搜索策略设计有效的B‐RafV600E抑制剂

B‐Raf激酶是促分裂原活化蛋白激酶（MAPK）信号传导途径中的重要中介，它可以将细胞外信号转化为细胞机制。该激酶的突变（例如，最常见的V600E突变）可导致ERK信号在病理上被激活，从而导致严重的疾病，例如躯体肿瘤。到目前为止，B-Raf抑制剂的开发取得了显着进展。但是，已广泛报道了批准的Raf药物的耐药性和复发情况，对旧药物进行优化和发现新抑制剂仍然是一项重要任务。在这项研究中，我们设计并评估了一系列新颖的B‐Raf ^V600E抑制剂。在使用MCSS策略（多副本模拟搜索）进行对接模拟之前，已经建立了一个片段库。重新组装适当的片段以提供新的候选化合物，然后通过迭代对接模拟和分子动力学对其进行进一步筛选。进行了生物测定以评估鉴定和合成的化合物的药理特性。结果表明，化合物5n具有令人印象深刻的酶抑制和抗增殖活性，表明在未来的研究中有希望的潜力。