Shahriary Alireza, Sisakht Mohsen, Arabfard Masoud, Behmard Esmaeil, Najafi Ali
Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
Iran J Med Sci. 2025 Mar 1;50(3):159-170. doi: 10.30476/ijms.2024.101737.3435. eCollection 2025 Mar.
Airway remodeling, a hallmark of chronic obstructive pulmonary disease (COPD) and mustard lung disease, is influenced by the Trefoil Factor 3 (TFF3). This study sought to pinpoint a compound with minimal toxicity that can effectively suppress TFF3 expression and activity.
We employed an integrative approach, combining gene expression analysis, molecular docking, and molecular dynamics simulations to identify potential TFF3 inhibitors. Gene expression analysis utilized Z-scores from the Library of Integrated Network-Based Cellular Signatures (LINCS) database to identify compounds altering TFF3 expression. Drug-like properties were assessed through Lipinski's "Rule of Five." Molecular docking was conducted with AutoDock Vina (version 1.1.2), and molecular dynamics simulations were performed using Groningen Machine for Chemical Simulations (GROMACS) version 5.1. Toxicity evaluation leveraged a Graph Convolutional Network (GCN). Statistical significance was set at P<0.05.
Eight of the compounds assessed significantly reduced TFF3 expression, with binding affinities (ΔG) ranging from -7 to -9.4 kcal/mol. Notably, genistein emerged as the frontrunner, showcasing potent TFF3 downregulation, minimal toxicity, and a robust inhibitory profile, as evidenced by molecular dynamics simulations. The significance of gene expression changes was indicated by Z-scores provided by the LINCS database rather than exact P values.
Genistein holds promise as a therapeutic agent for TFF3-mediated conditions, including mustard lung disease. Its potential to address the current therapeutic gaps is evident, but its clinical utility necessitates further and validation. A preprint of this article has already been published (https://assets.researchsquare.com/files/rs-3907985/v1/41b7e6e6-4d70-4573-81e6-4d5a913950bd.pdf?c=1707752778).
气道重塑是慢性阻塞性肺疾病（COPD）和芥子气肺病的一个标志，受三叶因子3（TFF3）影响。本研究旨在找出一种毒性最小且能有效抑制TFF3表达和活性的化合物。
我们采用了一种综合方法，结合基因表达分析、分子对接和分子动力学模拟来识别潜在的TFF3抑制剂。基因表达分析利用基于综合网络的细胞特征库（LINCS）数据库中的Z分数来识别改变TFF3表达的化合物。通过Lipinski的“五规则”评估类药物性质。使用AutoDock Vina（版本1.1.2）进行分子对接，并使用Groningen化学模拟机器（GROMACS）版本5.1进行分子动力学模拟。毒性评估利用图卷积网络（GCN）。统计学显著性设定为P<0.05。
评估的化合物中有8种显著降低了TFF3表达，结合亲和力（ΔG）范围为-7至-9.4千卡/摩尔。值得注意的是，染料木黄酮成为领先者，显示出强大的TFF3下调作用、最小的毒性和强大的抑制特征，分子动力学模拟证明了这一点。LINCS数据库提供的Z分数表明了基因表达变化的显著性，而非确切的P值。
染料木黄酮有望成为治疗TFF3介导的疾病（包括芥子气肺病）的治疗剂。其解决当前治疗差距的潜力显而易见，但其临床效用需要进一步研究和验证。本文的预印本已发表（https://assets.researchsquare.com/files/rs-3907985/v1/41b7e6e6-4d70-4573-81e6-4d5a913950bd.pdf?c=1707752778）。
