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Comprehensive Network Analysis Reveals the Targets and Potential Multitarget Drugs of Type 2 Diabetes Mellitus
Wan Zhou1, Qiang Liu2, Wei Wang1
1Laboratory for Diabetes, Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Abstract:
Type 2 diabetes mellitus (T2DM) is a metabolic disease with increasing prevalence and mortality year by year. The purpose of this study was to explore new therapeutic targets and candidate drugs for multitargets by single-cell RNA expression profile analysis, network pharmacology, and molecular docking. Single-cell RNA expression profiling of islet β cell samples between T2DM patients and nondiabetic controls was conducted to identify important subpopulations and the marker genes. The potential therapeutic targets of T2DM were identified by the overlap analysis of insulin-related genes and diabetes-related genes, the construction of protein-protein interaction network, and the molecular complex detection (MCODE) algorithm. The network distance method was employed to determine the potential drugs of the target. Molecular docking and molecular dynamic simulations were carried out using AutoDock Vina and Gromacs2019, respectively. Eleven cell clusters were identified by single-cell RNA sequencing (scRNA-seq) data, and three of them (C2, C8, and C10) showed significant differences between T2DM samples and normal samples. Eight genes from differential cell clusters were found from differential cell clusters to be associated with insulin activity and T2DM. The MCODE algorithm built six key subnetworks, with five of them correlating with inflammatory pathways and immune cell infiltration. Importantly, CCR5 was a gene within the key subnetworks and was differentially expressed between normal samples and T2DM samples, with the highest area under the ROC curve (AUC) of 82.5% for the diagnosis model. A total of 49 CCR5-related genes were screened, and DB05494 was identified as the most potential drug with the shortest distance to CCR5-related genes. Molecular docking illustrated that DB05494 stably bound with CCR5 (-8.0 kcal/mol) through multiple hydrogen bonds (LYS26, TYR37, TYR89, CYS178, and GLN280) and hydrophobic bonds (TRP86, PHE112, ILE198, TRP248, and TYR251). This study identified CCR5 as a potential therapeutic target and screened DB05494 as a potential drug for T2DM treatment.
Insights
This study identifies CCR5 as a potential therapeutic target for type 2 diabetes mellitus (T2DM). DB05494 shows promise as a drug candidate, demonstrating stable binding to CCR5 in molecular docking simulations for T2DM treatment.
Area of Science:
- Metabolomics and Systems Biology
- Genomics and Bioinformatics
- Pharmacology and Drug Discovery
Background:
- Type 2 diabetes mellitus (T2DM) is a growing global health concern with increasing prevalence and mortality.
- Identifying novel therapeutic targets and effective drugs is crucial for managing T2DM.
Purpose of the Study:
- To explore new therapeutic targets and candidate drugs for T2DM using integrated omics and computational approaches.
- To identify key molecular players and pathways involved in T2DM pathogenesis through single-cell RNA sequencing and network analysis.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of islet beta cells from T2DM patients and controls.
- Network pharmacology, including protein-protein interaction network construction and molecular complex detection (MCODE).
- Molecular docking and dynamic simulations to assess drug-target interactions.
Main Results:
- scRNA-seq identified distinct cell subpopulations and marker genes, with three clusters (C2, C8, C10) significantly differing between T2DM and normal samples.
- Eight differentially expressed genes associated with insulin activity and T2DM were identified.
- CCR5 emerged as a key target, showing differential expression and high diagnostic potential (AUC 82.5%).
- DB05494 was identified as a potential drug candidate, exhibiting stable binding to CCR5 via hydrogen and hydrophobic bonds.
Conclusions:
- CCR5 is a promising therapeutic target for T2DM.
- DB05494 represents a potential novel drug for T2DM treatment, warranting further investigation.
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