V600E-BRAF is a major protein target involved in various types of human cancers. However, the acquired resistance of the V600E-BRAF kinase to the vemurafenib and the side effects of other identified drugs initiate the search for efficient inhibitors. In the current paper, virtual docking screening combined with drug likeness and ADMET properties predictions were jointly applied to evaluate potent 2-(1H-imidazol-2-yl) pyridines as V600E-BRAF kinase inhibitors. Most of the studied compounds showed better docking scores and favorable interactions with theiV600E-BRAF target. Among the screened compounds, the two most potent (14 and 30) with good rerank scores (−124.079 and − 122.290) emerged as the most effective, and potent V600E-BRAF kinase inhibitors which performed better than vemurafenib (−116.174), an approved V600E-BRAF kinase inhibitor. Thus, the docking studies exhibited that these compounds have shown competing inhibition of V600E-BRAF kinase with vemurafenib at the active site and revealed better pharmacological properties based on Lipinski’s and Veber’s drug-likeness rules for oral bioavailability and ADMET properties. The docking result, drug-likeness rules, and ADMET parameters identified compounds (14 and 30) as the best hits against V600E-BRAF kinase with better pharmacological properties. This suggests that these compounds may be developed as potent V600E-BRAF inhibitors.

中文翻译：

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有效的 2-(1H-imidazol-2-yl) 吡啶衍生物作为潜在 V600E-BRAF 抑制剂的计算评估

V600E-BRAF 是涉及多种人类癌症的主要蛋白质靶标。然而，V600E-BRAF 激酶对 vemurafenib 的获得性耐药以及其他已鉴定药物的副作用启动了对有效抑制剂的寻找。在当前的论文中，虚拟对接筛选结合药物相似性和 ADMET 特性预测被联合应用于评估有效的 2-(1H-咪唑-2-基) 吡啶作为 V600E-BRAF 激酶抑制剂。大多数研究的化合物显示出更好的对接分数和与 iV600E-BRAF 目标的良好相互作用。在筛选的化合物中，两种最有效的（14 和 30）具有良好的 rerank 分数（-124.079 和 - 122.290）成为最有效、最有效的 V600E-BRAF 激酶抑制剂，其表现优于威罗菲尼 (-116.174)，已获批V600E-BRAF 激酶抑制剂。因此，对接研究表明，这些化合物在活性位点显示出对 V600E-BRAF 激酶的竞争性抑制，并根据 Lipinski 和 Veber 的口服生物利用度和 ADMET 特性的药物相似性规则显示出更好的药理特性。对接结果、药物相似性规则和 ADMET 参数确定化合物（14 和 30）是针对 V600E-BRAF 激酶的最佳命中，具有更好的药理特性。这表明这些化合物可能被开发为有效的 V600E-BRAF 抑制剂。药物相似性规则和 ADMET 参数将化合物（14 和 30）鉴定为具有更好药理学特性的 V600E-BRAF 激酶的最佳效果。这表明这些化合物可能被开发为有效的 V600E-BRAF 抑制剂。药物相似性规则和 ADMET 参数将化合物（14 和 30）鉴定为具有更好药理学特性的 V600E-BRAF 激酶的最佳效果。这表明这些化合物可能被开发为有效的 V600E-BRAF 抑制剂。