4.7 Article

Systems Approach to Pathogenic Mechanism of Type 2 Diabetes and Drug Discovery Design Based on Deep Learning and Drug Design Specifications

Journal

Publisher

MDPI
DOI: 10.3390/ijms22010166

Keywords

type 2 diabetes (T2D); pathogenic mechanism; deep neural network (DNN)-based DTI model; pathogenic biomarkers; drug design specification; multiple-molecule targeting drug

Funding

  1. Ministry of Science and Technology [MOST 107-2221-E-007-112-MY3]

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This study proposed a systems biology approach to investigate the pathogenic mechanism for type 2 diabetes and developed a systematic drug discovery strategy for designing a potential multiple-molecule targeting drug. By integrating databases, constructing genome-wide networks, and identifying core signaling pathways, significant biomarkers were identified as drug targets, and potential drugs suitable for T2D were sieved out based on design specifications and a deep neural network model predicting drug-target interactions.
In this study, we proposed a systems biology approach to investigate the pathogenic mechanism for identifying significant biomarkers as drug targets and a systematic drug discovery strategy to design a potential multiple-molecule targeting drug for type 2 diabetes (T2D) treatment. We first integrated databases to construct the genome-wide genetic and epigenetic networks (GWGENs), which consist of protein-protein interaction networks (PPINs) and gene regulatory networks (GRNs) for T2D and non-T2D (health), respectively. Second, the relevant real GWGENs are identified by system identification and system order detection methods performed on the T2D and non-T2D RNA-seq data. To simplify network analysis, principal network projection (PNP) was thereby exploited to extract core GWGENs from real GWGENs. Then, with the help of KEGG pathway annotation, core signaling pathways were constructed to identify significant biomarkers. Furthermore, in order to discover potential drugs for the selected pathogenic biomarkers (i.e., drug targets) from the core signaling pathways, not only did we train a deep neural network (DNN)-based drug-target interaction (DTI) model to predict candidate drug's binding with the identified biomarkers but also considered a set of design specifications, including drug regulation ability, toxicity, sensitivity, and side effects to sieve out promising drugs suitable for T2D.

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