The resistance of V600E-BRAF to the vemurafenib and the side effects of the identified inhibitors trigger the research for a novel and more potent anti-melanoma agents. In this study, virtual docking screening along with pharmacokinetics ADMET and drug-likeness predictions were combined to evaluate some 4-(quinolin-2-yl)pyrimidin-2-amine derivatives as potent V600E-BRAF inhibitors. Some of the selected compounds exhibited better binding scores and favorable interaction with the V600E-BRAF enzyme. Out of the screened compounds, two most potent (5 and 9) having good Rerank scores (− 128.011 and − 126.258) emerged as effective and potent V600E-BRAF inhibitors that outperformed the FDA-approved V600E-BRAF inhibitor (vemurafenib, − 118.607). Thus, the molecular docking studies revealed that the studied compounds showed competing for inhibition of V600E-BRAF with vemurafenib at the binding site and possessed better pharmacological parameters based on the drug-likeness rules filters for the oral bioavailability, and ADMET risk parameters. The docking analysis, drug-likeness rules filters, and ADMET study identified compounds (5 and 9) as the best hits against V600E-BRAF kinase with enhanced pharmacological properties. This recommends that these compounds may be developed as potent anti-melanoma agents.

中文翻译：

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在计算机上评估某些4-（喹啉-2-基）嘧啶-2-胺衍生物作为强效V600E-BRAF抑制剂的药代动力学ADMET和药物相似性预测

V600E-BRAF对维罗非尼的耐药性和已确定的抑制剂的副作用触发了对新型和更有效的抗黑素瘤药物的研究。在这项研究中，虚拟对接筛选与药代动力学ADMET和药物相似性预测相结合，以评估作为有效V600E-BRAF抑制剂的一些4-（喹啉-2-基）嘧啶-2-胺衍生物。某些选定的化合物表现出更好的结合力和与V600E-BRAF酶的良好相互作用。在筛选出的化合物中，有两个最有效的Rerank得分最高的（5和9）（-128.011和-126.258）成为有效且有效的V600E-BRAF抑制剂，其性能优于FDA批准的V600E-BRAF抑制剂（vemurafenib，-118.607） 。从而，分子对接研究表明，所研究的化合物表现出在结合位点与维拉非尼竞争抑制V600E-BRAF的作用，并且基于口服生物利用度的药物相似性规则过滤器和ADMET风险参数，具有更好的药理参数。对接分析，药物相似性规则过滤器和ADMET研究确定了化合物（5和9）是对抗V600E-BRAF激酶的最佳药物，具有增强的药理特性。建议将这些化合物开发为有效的抗黑素瘤药物。ADMET研究确定了化合物（5和9）是对抗V600E-BRAF激酶的最佳药物，具有增强的药理特性。建议将这些化合物开发为有效的抗黑素瘤药物。ADMET研究确定了化合物（5和9）是对抗V600E-BRAF激酶的最佳药物，具有增强的药理特性。建议将这些化合物开发为有效的抗黑素瘤药物。