Identification of novel natural compounds against CFTR p.Gly628Arg pathogenic variant.

IF 3.5 3区 生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY AMB Express Pub Date : 2024-09-09 DOI:10.1186/s13568-024-01762-9
Muhammad Umer Khan, Azra Sakhawat, Raima Rehman, Abbas Haider Wali, Muhammad Usman Ghani, Areeba Akram, Muhammad Arshad Javed, Qurban Ali, Zhou Yu-Ming, Daoud Ali, Zhou Yu-Ming
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Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) protein is an ion channel found in numerous epithelia and controls the flow of water and salt across the epithelium. The aim of our study to find natural compounds that can improve lung function for people with cystic fibrosis (CF) caused by the p.Gly628Arg (rs397508316) mutation of CFTR protein. The sequence of CFTR protein as a target structure was retrieved from UniProt and PDB database. The ligands that included Armepavine, Osthole, Curcumin, Plumbagine, Quercetin, and one Trikafta (R*) reference drug were screened out from PubChem database. Autodock vina software carried out docking, and binding energies between the drug and the target were included using docking-score. The following tools examined binding energy, interaction, stability, toxicity, and visualize protein-ligand complexes. The compounds having binding energies of -6.4, -5.1, -6.6, -5.1, and - 6.5 kcal/mol for Armepavine, Osthole, Curcumin, Plumbagine, Quercetin, and R*-drug, respectively with mutated CFTR (Gly628Arg) structure were chosen as the most promising ligands. The ligands bind to the mutated CFTR protein structure active sites in hydrophobic bonds, hydrogen bonds, and electrostatic interactions. According to ADMET analyses, the ligands Armepavine and Quercetin also displayed good pharmacokinetic and toxicity characteristics. An MD simulation for 200 ns was also established to ensure that Armepavine and Quercetin ligands attached to the target protein favorably and dynamically, and that protein-ligand complex stability was maintained. It is concluded that Armepavine and Quercetin have stronger capacity to inhibit the effect of mutated CFTR protein through improved trafficking and restoration of original function.

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针对 CFTR p.Gly628Arg 致病变体的新型天然化合物的鉴定。
囊性纤维化跨膜传导调节因子(CFTR)蛋白是一种存在于多种上皮细胞中的离子通道,可控制水和盐在上皮细胞中的流动。我们的研究旨在寻找能改善因 CFTR 蛋白 p.Gly628Arg (rs397508316) 突变而导致的囊性纤维化(CF)患者肺功能的天然化合物。研究人员从 UniProt 和 PDB 数据库中获取了 CFTR 蛋白的序列作为目标结构。从 PubChem 数据库中筛选出的配体包括 Armepavine、Osthole、Curcumin、Plumbagine、Quercetin 和一种 Trikafta (R*) 参考药物。Autodock vina 软件进行了对接,并使用 docking-score 计算了药物与目标物之间的结合能。以下工具检测了结合能、相互作用、稳定性、毒性以及蛋白质配体复合物的可视化。研究人员选择了与突变 CFTR(Gly628Arg)结构的 Armepavine、Osthole、Curcumin、Plumbagine、Quercetin 和 R*-drug 的结合能分别为 -6.4、-5.1、-6.6、-5.1 和 -6.5 kcal/mol 的化合物作为最有希望的配体。这些配体通过疏水键、氢键和静电作用与突变的 CFTR 蛋白结构活性位点结合。根据 ADMET 分析,配体 Armepavine 和 Quercetin 也显示出良好的药代动力学和毒性特征。此外,还建立了 200 ns 的 MD 模拟,以确保 Armepavine 和 Quercetin 配体与目标蛋白质的良好动态连接,并保持蛋白质-配体复合物的稳定性。结果表明,Armepavine 和 Quercetin 能通过改善转运和恢复原有功能来抑制变异 CFTR 蛋白的作用。
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来源期刊
AMB Express
AMB Express BIOTECHNOLOGY & APPLIED MICROBIOLOGY-
CiteScore
7.20
自引率
2.70%
发文量
141
审稿时长
13 weeks
期刊介绍: AMB Express is a high quality journal that brings together research in the area of Applied and Industrial Microbiology with a particular interest in ''White Biotechnology'' and ''Red Biotechnology''. The emphasis is on processes employing microorganisms, eukaryotic cell cultures or enzymes for the biosynthesis, transformation and degradation of compounds. This includes fine and bulk chemicals, polymeric compounds and enzymes or other proteins. Downstream processes are also considered. Integrated processes combining biochemical and chemical processes are also published.
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