Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02 097 Warsaw, Poland.
Department of Toxicology and Food Science, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02 097 Warsaw, Poland.
Molecules. 2023 Jul 7;28(13):5273. doi: 10.3390/molecules28135273.
BRAF inhibitors have improved the treatment of advanced or metastatic melanoma in patients that harbor a BRAF mutation. Because of new insights into the role of aberrant glycosylation in drug resistance, we designed and studied three novel vemurafenib derivatives possessing pentose-associated aliphatic ligands-methyl-, ethyl-, and isopropyl-ketopentose moieties-as potent BRAF kinase inhibitors. The geometries of these derivatives were optimized using the density functional theory method. Molecular dynamic simulations were performed to find interactions between the ligands and BRAF kinase. Virtual screening was performed to assess the fate of derivatives and their systemic toxicity, genotoxicity, and carcinogenicity. The computational mapping of the studied ligand-BRAF complexes indicated that the central pyrrole and pyridine rings of derivatives were located within the hydrophobic ATP-binding site of the BRAF protein kinase, while the pentose ring and alkyl chains were mainly included in hydrogen bonding interactions. The isopropyl-ketopentose derivative was found to bind the BRAF oncoprotein with more favorable energy interaction than vemurafenib. ADME-TOX in silico studies showed that the derivatives possessed some desirable pharmacokinetic and toxicologic properties. The present results open a new avenue to study the carbohydrate derivatives of vemurafenib as potent BRAF kinase inhibitors to treat melanoma.
BRAF 抑制剂改善了携带 BRAF 突变的晚期或转移性黑色素瘤患者的治疗效果。由于对异常糖基化在耐药性中的作用有了新的认识，我们设计并研究了三种新型具有戊糖相关脂肪族配体（甲基、乙基和异丙基酮戊糖部分）的vemurafenib 衍生物，作为有效的 BRAF 激酶抑制剂。使用密度泛函理论方法优化了这些衍生物的几何形状。进行分子动力学模拟以找到配体与 BRAF 激酶之间的相互作用。进行虚拟筛选以评估衍生物的命运及其全身毒性、遗传毒性和致癌性。研究配体-BRAF 复合物的计算映射表明，衍生物的中央吡咯烷和吡啶环位于 BRAF 蛋白激酶的疏水性 ATP 结合位点内，而戊糖环和烷基链主要包含氢键相互作用。与 vemurafenib 相比，异丙基酮戊糖衍生物被发现与 BRAF 癌蛋白具有更有利的能量相互作用。基于计算机的 ADME-TOX 研究表明，这些衍生物具有一些理想的药代动力学和毒理学特性。目前的结果为研究作为治疗黑色素瘤的有效 BRAF 激酶抑制剂的vemurafenib 的碳水化合物衍生物开辟了新途径。
