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Identification of novel inhibitors of DDR1 against idiopathic pulmonary fibrosis by integrative transcriptome meta-analysis, computational and experimental screening.
- Source :
-
Molecular bioSystems [Mol Biosyst] 2016 Apr 26; Vol. 12 (5), pp. 1540-51. - Publication Year :
- 2016
-
Abstract
- Idiopathic pulmonary fibrosis (IPF) is a kind of a chronic and fatal lung disease leading to progressive lung function decline. Although several RNA microarray studies on IPF patients have been reported, their results were merely specific to each study with distinct platforms or sample types. In the current study, an integrative transcriptome meta-analysis of IPF was performed to explore regulated pathways, based on four independent expression profiling microarrays of IPF datasets, including 73 samples from IPF tissues or lung fibroblast cells. The results suggested the discoidin domain receptor 1 (DDR1) and downstream c-Jun N-terminal kinases (JNK) pathway may play important roles in the progression of IPF. To our knowledge, discoidin domain receptor 1 (DDR1) is a kind of receptor tyrosine kinase (RTK) with a unique ability to bind both fibrillar and non-fibrillar collagens. Based on the crystallographic structures of DDR1, the combination of molecular dynamics simulation and a hybrid protocol of a virtual screening method, comprised of PBVS (multicomplex-pharmacophore based virtual screening) and DBVS (docking based virtual screening) methods were used for retrieving novel DDR1 inhibitors from the SPECS database. Twelve hit compounds were selected from the hit compounds and shifted to experimental validations, and the most potent compound was evaluated for its anti-IPF capacity on murine IPF models. Thus, these results may provide valuable information for further discovery of potential lead compounds for IPF therapy.
- Subjects :
- Animals
Computer Simulation
Discoidin Domain Receptor 1 antagonists & inhibitors
Disease Models, Animal
Female
Gene Expression Profiling
Humans
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Idiopathic Pulmonary Fibrosis chemically induced
Idiopathic Pulmonary Fibrosis drug therapy
Idiopathic Pulmonary Fibrosis metabolism
Molecular Conformation
Molecular Dynamics Simulation
Molecular Structure
Protein Kinase Inhibitors pharmacology
Rats
Workflow
Computational Biology methods
Discoidin Domain Receptor 1 chemistry
Discoidin Domain Receptor 1 genetics
Drug Discovery methods
Idiopathic Pulmonary Fibrosis genetics
Protein Kinase Inhibitors chemistry
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 1742-2051
- Volume :
- 12
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular bioSystems
- Publication Type :
- Academic Journal
- Accession number :
- 26956955
- Full Text :
- https://doi.org/10.1039/c5mb00911a