title: Potent inhibition of TGF-β signaling pathway regulator Abl: potential therapeutics for hepatic fibrosis.
abstract: Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The treatment of hepatic fibrosis is still difficult and remains a challenge to the clinician. In recent years, the TGF-β signaling pathway regulator tyrosine kinase Abl has been raised as a new and promising target of hepatic fibrosis therapy. Here, considering that there are numerous drugs and drug-like compounds being approved or under clinical development and experimental investigation, it is expected that some of the existing drugs can be re-exploited as new agents to target Abl with the capability of suppressing hepatic fibrosis. To achieve this, a synthetic protocol that integrated molecular docking, affinity scoring dynamics simulation and free energy analysis was described to systematically profile the inhibitory potency of various drugs and drug-like compounds against the kinase domain of Abl. Consequently, 4 out of 13 tested drug candidates were successfully identified to have high-Abl inhibitory activities. By visually examining the dynamics behavior, structural basis and energetic property of few typical Abl-drug complex cases, a significantly different pattern of non-bonded interactions between the binding of active and inactive drug ligands to Abl receptor was revealed; the former is defined by strong, specific chemical forces, while the latter can only form non-specific hydrophobic contacts with slight atomic collisions.
authors.affiliation: a Institute of Cell Biology, Zhejiang University , Hangzhou P.R. China and.|b Infectious Department , Taizhou Hospital, Affiliated Hospital of Wenzhou Medical University , Taizhou , P.R. China.
authors.forename: Kuifeng
authors.initials: K
authors.lastname: Wang
authors.affiliation: b Infectious Department , Taizhou Hospital, Affiliated Hospital of Wenzhou Medical University , Taizhou , P.R. China.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Tang
authors.affiliation: b Infectious Department , Taizhou Hospital, Affiliated Hospital of Wenzhou Medical University , Taizhou , P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yan
authors.affiliation: b Infectious Department , Taizhou Hospital, Affiliated Hospital of Wenzhou Medical University , Taizhou , P.R. China.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Zhu
authors.affiliation: a Institute of Cell Biology, Zhejiang University , Hangzhou P.R. China and.
authors.forename: Jicheng
authors.initials: J
authors.lastname: Li
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000517:prevention & control; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000648:ultrastructure*; D016212:Transforming Growth Factor beta / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl
keywords: Abl kinase; TGF-β signaling pathway; hepatic fibrosis