title: Identification of novel inhibitors of DDR1 against idiopathic pulmonary fibrosis by integrative transcriptome meta-analysis, computational and experimental screening.
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.
authors.affiliation: School of Pharmacy and the First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610050, P. R. China. jiangqinglin@cmc.edu.cn.
authors.forename: Can
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Pharmacy and the First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610050, P. R. China. jiangqinglin@cmc.edu.cn.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Deng
authors.affiliation: School of Pharmacy and the First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610050, P. R. China. jiangqinglin@cmc.edu.cn and Department of Public Health, Chengdu Medical College, Chengdu, 610050, P. R. China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yu
authors.affiliation: State Key laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Fengbo
authors.initials: F
authors.lastname: Wu
authors.affiliation: State Key laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Men
authors.affiliation: School of Pharmacy and the First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610050, P. R. China. jiangqinglin@cmc.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: School of Pharmacy and the First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610050, P. R. China. jiangqinglin@cmc.edu.cn and Department of Public Health, Chengdu Medical College, Chengdu, 610050, P. R. China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Gastroenterology, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, 610065, P. R. China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmacy and the First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, 610050, P. R. China. jiangqinglin@cmc.edu.cn and State Key laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Jiang
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D000070819:Discoidin Domain Receptor 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics*; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D059467:Transcriptome; D057188:Workflow
chemical_list: D047428:Protein Kinase Inhibitors; D000070819:Discoidin Domain Receptor 1