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

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.