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.
Keywords: Abl kinase; TGF-β signaling pathway; hepatic fibrosis.