Melanoma cancer causes serious health problem worldwide because of its rapid invasion to other organs and lack of satisfactory chemotherapy. The pGI50 anticancer activity values of 70 compounds from the NCI (National Cancer Institute) on MALME-3M cell line was modeled to describe the quantitative structure-activity relationships (QSARs) of the compounds, and some selected compounds were docked. The generated QSAR model was found to be statistically significant based on the obtained values of the validation keys such as R2 (0.885), Radjusted2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {R}_{\mathrm{adjusted}}^2 $$\end{document} (0.868), Q2cv (0.842), and Rpred2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {R}_{pred}^2 $$\end{document} (0.738) required to evaluate the strength and robustness of QSAR model. Compound 39 was selected as a template due to its good pGI50 (9.205) and was modified to design new potent compounds. The predicted pGI50 activity of the designed compounds by the built model was N1 (9.836), N2 (12.876), N3 (10.901), and N4 (11.263) respectively. These proposed compounds were docked with V600E-BRAF receptor and the result shows that, N1, N2, N3, and N4 with free binding energy (FBE) of − 11.7 kcal mol−1, − 12.8 kcal mol−1, − 12.7 kcal mol−1, and − 12.9 kcal mol−1 respectively were better than the parent structure of the template (compound 39, FBE = − 7.0 kcal mol−1) and the standard V600E-BRAF inhibitor (Vemurafenib, FBE = − 11.3 kcal mol−1). Additionally, these compounds passed the drug-likeness criteria successfully to be orally bioavailable. The proposed compounds were considered optimal as their performances are comparable to vemurafenib and possessed enhanced physicochemical properties. Thus recommends further research such as synthesis, in vivo, and ex-vivo evaluation.

中文翻译：

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一些新型抗癌化合物对MALME-3M黑色素瘤细胞系的配体药物设计和分子对接模拟研究

由于黑色素瘤对其他器官的快速侵袭和缺乏令人满意的化疗，黑色素瘤在世界范围内引起严重的健康问题。对来自 NCI（美国国家癌症研究所）的 70 种化合物对 MALME-3M 细胞系的 pGI50 抗癌活性值进行建模，以描述化合物的定量构效关系 (QSAR)，并对接了一些选定的化合物。基于 R2 (0.885)、Radjusted2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} 等验证键的获得值，发现生成的 QSAR 模型具有统计显着性\usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {R}_{\mathrm{adjusted}}^2 $$\end{document} (0.868), Q2cv (0.842), 和 Rpred2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin }{-69pt} \begin{document}$$ {R}_{pred}^2 $$\end{document} (0.738) 需要评估 QSAR 模型的强度和稳健性。化合物 39 因其良好的 pGI50 (9.205) 被选为模板，并被修改以设计新的有效化合物。通过建立的模型预测的设计化合物的 pGI50 活性分别为 N1 (9.836)、N2 (12.876)、N3 (10.901) 和 N4 (11.263)。这些提议的化合物与 V600E-BRAF 受体对接，结果表明，N1、N2、N3 和 N4 的自由结合能 (FBE) 为 - 11.7 kcal mol-1、- 12.8 kcal mol-1、- 12.7 kcal mol −1 和 − 12。9 kcal mol-1 分别优于模板的母体结构（化合物 39，FBE = - 7.0 kcal mol-1）和标准 V600E-BRAF 抑制剂（Vemurafenib，FBE = - 11.3 kcal mol-1）。此外，这些化合物成功通过了药物相似性标准，可口服生物利用。所提出的化合物被认为是最佳的，因为它们的性能与威罗菲尼相当，并且具有增强的理化特性。因此建议进一步研究，如合成、体内和体外评估。所提出的化合物被认为是最佳的，因为它们的性能与威罗菲尼相当，并且具有增强的理化特性。因此建议进一步研究，如合成、体内和体外评估。所提出的化合物被认为是最佳的，因为它们的性能与威罗菲尼相当，并且具有增强的理化特性。因此建议进一步研究，如合成、体内和体外评估。