Transcriptomic-Guided Molecular Docking Identifies CCR۲ and CCR۵ as Therapeutic Targets for Drug Repurposing in Metabolic Aging and Type ۲ Diabetes

Background: Metabolic aging is characterized by chronic low-grade inflammation (inflammaging) that drives insulin resistance and progression to type ۲ diabetes (T۲D). The chemokine receptors CCR۲ and CCR۵ have been implicated in aging-associated immune-cell recruitment within adipose tissue, positioning them as candidate therapeutic targets. However, transcriptomics-guided identification of membrane-associated therapeutic targets followed by structure-based evaluation of natural compounds remains limited in metabolic aging. Methods: An integrated transcriptomic and structure-based computational workflow was applied. RNA-sequencing data from human adipose tissue of young and aged donors (GEO: GSE۱۷۵۴۹۵) were analyzed using DESeq۲ to identify differentially expressed genes (DEGs). Gene Ontology (GO) enrichment analysis and membrane-localization filtering were used to prioritize druggable candidates, followed by protein–protein interaction analysis using STRING and cytoHubba. CCR۲ (PDB ID: ۶GPX) and CCR۵ (PDB ID: ۴MBS) were selected for molecular docking against five natural bioactive compounds (berberine, silibinin, resveratrol, quercetin, and curcumin) using AutoDock Vina in PyRx, with the docking protocol validated by redocking the co-crystallized native ligands. Results: Among ۲۷,۸۲۴ expressed genes, ۱,۷۵۰ DEGs were identified between aged and young adipose tissue. Membrane-localization filtering reduced these candidates to ۹۳ membrane-associated DEGs, from which network analysis prioritized CCR۲ and CCR۵ for downstream structure-based evaluation. CCR۲ was significantly upregulated (log۲FC = ۱.۷۰, adjusted P = ۰.۰۱۹), while CCR۵ also exhibited significant upregulation (log۲FC = ۱.۲۱, adjusted P = ۰.۰۰۶). Network analysis identified CCR۵ as one of the highest-ranked hub genes based on the MCC algorithm, whereas CCR۲ was also prioritized among the top-ranked membrane-associated genes. Redocking of the native ligands MRV (CCR۵) and F۷N (CCR۲) yielded binding affinities of −۱۲.۲ and −۱۰.۹ kcal/mol, respectively, confirming the validity of the docking protocol. Silibinin showed the strongest predicted binding affinity toward both receptors (CCR۲: −۹.۳ kcal/mol; CCR۵: −۱۰.۳ kcal/mol), showing higher predicted binding affinities than curcumin, berberine, quercetin, and resveratrol. Conclusion: This integrated transcriptomic and structure-based analysis identifies CCR۲ and CCR۵ as biologically relevant therapeutic targets in metabolic aging and highlights silibinin as a promising dual-target natural modulator. These findings provide a biological rationale for future experimental validation of CCR۲/CCR۵-targeted interventions in age-associated metabolic inflammation and type ۲ diabetes.

کلیدواژه ها:

Metabolic aging ، Type ۲ diabetes ، Transcriptomics ، Membrane proteins ، CCR۲ ، CCR۵ ، Molecular docking ، Silibinin