Discovering promising drug candidates for Parkinson’s disease: integrating miRNA and DEG analysis with molecular dynamics and MMPBSA

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Bisma Ishtiaq, Rehan Zafar Paracha, Maryum Nisar, Saima Ejaz, Zamir Hussain
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Abstract

Parkinson’s disease (PD) is a progressive neurological disorder with an increasing prevalence in aging populations. Identifying effective therapeutic targets and treatments remains a critical challenge. This study aimed to discover potential therapeutic targets and design novel compounds for PD treatment. Gene expression analysis was conducted using diverse datasets, including microarray, mRNA sequencing, and miRNA sequencing. While no common genes were identified across all datasets, the RNA-seq dataset GSE-135036 was prioritized. The investigation focused on downregulated miRNAs targeting upregulated mRNAs, revealing that hsa-mir-5585 regulates Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) within the Shigellosis pathway. Given RIPK1’s role in cell death and inflammation, it emerged as a promising therapeutic target for PD. To identify RIPK1 inhibitors, 67 compounds were screened via molecular docking, with CHEMBL-3109201 exhibiting the highest binding affinity. A structurally similar compound, CHEMBL-76328382, also demonstrated strong interactions. A fragment-based drug design approach generated two novel compounds, BI-1215 and BI-146, which, along with RIPK1-IN-4 and CHEMBL-70909876, were shortlisted based on docking scores and ADME profiles. Molecular dynamics simulations confirmed the stability of CHEMBL-70909876 and BI-1215, with RMSD fluctuations between 0.005 and 0.2 nm. MM-PBSA analysis further validated their superior thermodynamic stability and binding affinity compared to other candidates. This study offers novel insights into PD pathogenesis and potential therapeutic interventions, marking a significant step toward effective treatment strategies for this debilitating disorder.

发现有希望的帕金森病候选药物:将miRNA和DEG分析与分子动力学和MMPBSA相结合
帕金森病(PD)是一种进行性神经系统疾病,在老年人群中患病率越来越高。确定有效的治疗靶点和治疗方法仍然是一个关键的挑战。本研究旨在发现潜在的治疗靶点并设计新的PD治疗药物。基因表达分析使用多种数据集进行,包括微阵列、mRNA测序和miRNA测序。虽然所有数据集中没有发现共同基因,但RNA-seq数据集GSE-135036被优先考虑。该研究聚焦于靶向上调mrna的下调miRNAs,揭示hsa-mir-5585在志贺氏菌病途径中调控受体相互作用丝氨酸/苏氨酸蛋白激酶1 (RIPK1)。鉴于RIPK1在细胞死亡和炎症中的作用,它成为PD的一个有希望的治疗靶点。为了鉴定RIPK1抑制剂,通过分子对接筛选了67个化合物,其中CHEMBL-3109201表现出最高的结合亲和力。一个结构相似的化合物CHEMBL-76328382也表现出很强的相互作用。基于片段的药物设计方法产生了两种新化合物BI-1215和BI-146,它们与RIPK1-IN-4和CHEMBL-70909876一起,根据对接评分和ADME谱入围。分子动力学模拟证实了CHEMBL-70909876和BI-1215的稳定性,RMSD波动在0.005 ~ 0.2 nm之间。MM-PBSA分析进一步验证了它们与其他候选化合物相比具有更好的热力学稳定性和结合亲和力。这项研究为帕金森病的发病机制和潜在的治疗干预提供了新的见解,标志着对这种衰弱性疾病的有效治疗策略迈出了重要的一步。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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