熊果酸与转录因子 BRAF、V600E 和 V600K 的相互作用:一种针对潜在黑色素瘤新疗法的计算方法。

IF 2.1 4区 化学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Giovanny Aguilera-Durán, Stephanie Hernández-Castro, Brenda V. Loera-García, Alex Rivera-Vargas, J. M. Alvarez-Baltazar, Ma Del Refugio Cuevas-Flores, Antonio Romo-Mancillas
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引用次数: 0

摘要

背景:黑色素瘤是死亡率最高的癌症之一,因为它具有转移能力。目前已对多个靶点进行了研究,以开发针对这种病症的药物。其中一个主要靶点是激酶 BRAF(RAF,快速加速纤维肉瘤)。黑色素瘤中最常见的突变是 BRAFV600E,据报道,50%-90% 的黑色素瘤患者都存在这种突变。由于 BRAFV600E 突变的相关性,已经开发出了这种激酶的抑制剂,即 vemurafenib-OMe 和 dabrafenib。熊果酸(UA)是一种五环三萜类化合物,具有特殊的结构--五环支架,因此具有广泛的生物活性;研究最多的是其抗癌能力。在这项工作中,我们报告了 vemurafenib-Ome、dabrafenib 和 UA 的相互作用谱,以确定 UA 是否具有与 BRAFWT、BRAFV600E 和 BRAFV600K 结合的能力。我们对 BRAFWT、V600E 和 V600K 进行了同源建模、分子对接和分子动力学模拟,并获得了与抑制剂结合相关的相互作用和残基。我们发现,UA 与抑制剂一样,与 I463、Q530、C532 和 F583 存在氢键相互作用、范德华疏水相互作用和 π 堆积。熊果酸与 BRAFV600K 复合物的ΔG(- 63.31 kcal/mol)与选择性抑制剂达拉非尼与 BRAFV600K 复合物的ΔG(- 63.32 kcal/mol)相当,与 vemurafenib-OMe 与 BRAFWT 和 V600E 复合物的ΔG 相似。有了这些信息,熊果酸可作为先导化合物进行循环设计,并优化其与突变的结合情况和选择性,从而开发出针对 BRAFV600E 和 V600K 的新型选择性抑制剂,用于潜在的黑色素瘤新疗法:同源建模计算在公共服务器 I-TASSER 和 ROBETTA 上进行,然后使用 AutoGrid 4.2.6、AutoDockGPU 1.5.3 和 AutoDockTools 1.5.6 进行分子对接计算。分子动力学和元动力学模拟是在 Schrödinger-Maestro 2020-4 程序学术版的 Desmond 模块中利用 OPLS-2005 力场进行的。配体与蛋白质之间的相互作用是通过薛定谔-马埃斯特罗程序、LigPlot + 和 PLIP(蛋白质-配体相互作用剖析器)进行评估的。最后,本文中展示的所有蛋白质图像都是用 PyMOL 程序绘制的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ursolic acid interaction with transcription factors BRAF, V600E, and V600K: a computational approach towards new potential melanoma treatments

Context

Melanoma is one of the cancers with the highest mortality rate for its ability to metastasize. Several targets have undergone investigation for the development of drugs against this pathology. One of the main targets is the kinase BRAF (RAF, rapidly accelerated fibrosarcoma). The most common mutation in melanoma is BRAFV600E and has been reported in 50–90% of patients with melanoma. Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ursolic acid (UA) is a pentacyclic triterpene with a privileged structure, the pentacycle scaffold, which allows to have a broad variety of biological activity; the most studied is its anticancer capacity. In this work, we reported the interaction profile of vemurafenib-OMe, dabrafenib, and UA, to define whether UA has binding capacity to BRAFWT, BRAFV600E, and BRAFV600K. Homology modeling of BRAFWT, V600E, and V600K; molecular docking; and molecular dynamics simulations were carried out and interactions and residues relevant to the binding of the inhibitors were obtained. We found that UA, like the inhibitors, presents hydrogen bond interactions, and hydrophobic interactions of van der Waals, and π-stacking with I463, Q530, C532, and F583. The ΔG of ursolic acid in complex with BRAFV600K (− 63.31 kcal/mol) is comparable to the ΔG of the selective inhibitor dabrafenib (− 63.32 kcal/mol) in complex to BRAFV600K and presents a ΔG like vemurafenib-OMe with BRAFWT and V600E. With this information, ursolic acid could be considered as a lead compound for design cycles and to optimize the binding profile and the selectivity towards mutations for the development of new selective inhibitors for BRAFV600E and V600K to new potential melanoma treatments.

Methods

The homology modeling calculations were executed on the public servers I-TASSER and ROBETTA, followed by molecular docking calculations using AutoGrid 4.2.6, AutoDockGPU 1.5.3, and AutoDockTools 1.5.6. Molecular dynamics and metadynamics simulations were performed in the Desmond module of the academic version of the Schrödinger-Maestro 2020–4 program, utilizing the OPLS-2005 force field. Ligand–protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein–ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.

Graphical Abstract

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来源期刊
Journal of Molecular Modeling
Journal of Molecular Modeling 化学-化学综合
CiteScore
3.50
自引率
4.50%
发文量
362
审稿时长
2.9 months
期刊介绍: The Journal of Molecular Modeling focuses on "hardcore" modeling, publishing high-quality research and reports. Founded in 1995 as a purely electronic journal, it has adapted its format to include a full-color print edition, and adjusted its aims and scope fit the fast-changing field of molecular modeling, with a particular focus on three-dimensional modeling. Today, the journal covers all aspects of molecular modeling including life science modeling; materials modeling; new methods; and computational chemistry. Topics include computer-aided molecular design; rational drug design, de novo ligand design, receptor modeling and docking; cheminformatics, data analysis, visualization and mining; computational medicinal chemistry; homology modeling; simulation of peptides, DNA and other biopolymers; quantitative structure-activity relationships (QSAR) and ADME-modeling; modeling of biological reaction mechanisms; and combined experimental and computational studies in which calculations play a major role.
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