Allium sativum bioactives modulate AGE- RAGE signalling pathway to attenuate diabetic microvascular complications: An integrative computational pharmacogenomics approach

Abstract

Aim & objective

To explore the action mechanism of phytochemicals found in allium sativum in treating diabetic microvascular complication based on molecular docking, theoretical prediction, network pharmacology, pharmacogenomics and gene expression analysis.

Methods

A total of 112 phytochemical from allium sativum were docked and selected phytochemicals were checked for their physiochemical properties and theoretical prediction. After shortlisting, phytochemical disease targets related to Diabetic Microvascular Complications (DMVC) were identified and integrated with compound-target interactions to construct a comprehensive compound-target-disease network. This network was analysed for core targets and hub genes with subsequent pathway enrichment. Construction of protein-protein interaction (PPI) (using cytoscape), Gene Ontology functional analysis and KEGG pathway analysis, followed by gene expression analysis from Gene Expression Omnibus using accession ID GSE251645 through GEO query limma R packages to elucidate the therapeutic mechanisms.

Results

A total of 60 bioactive components from allium sativum exhibited excellent binding energies (>-4 kcal/mol). Twelve candidate compounds passed further screening and were linked to 914 target genes. Disease target analysis identified 2372 DMVC related genes. Core target analysis revealed 874 common targets between drug and disease, suggesting strong interactions and potential therapeutic relevance. PPI (Protein Protein interaction) network analysis identified key hub genes, including ESR1, MTOR, HSP90AA1, and others critical to DMVC pathology. GO and KEGG enrichment analyses highlighted significant biological processes and pathways including AGE-RAGE signalling. From GEO, differential gene expression (DEG) analysis provided insights into the significant regulation of genes related to DMVC, Genes such as MAPK3, NR1H2, CDK4, NOS3, GYS1, RELA, SLC2A, MMP28, PIM1, and PYGL were found to be down-regulated, while PIK3LA, PIK3RI, MAPKI, GSK3B, MAPK8, TGFBRI, JAK2, and PIK3LB were found to be up-regulated.

Conclusion

This study presents the first-ever comprehensive drug discovery pipeline targeting diabetic microvascular complications (DMVC) using Allium sativum. By integrating virtual screening, molecular docking, cheminformatics, toxicity prediction, pharmacogenomics, pathway, network analysis, gene expression analysis and in silico multi-omics integration, this study unveil novel molecular mechanisms for DMVC involving the AGE-RAGE signalling pathway using allium sativum. Thus, these findings offer an unprecedented framework for further experimental validation and potential drug development.