Computer‐Assisted Identification of Inhibitor with Novel Pharmacophore Targeting First Kringle Domain of Hepatocyte Growth Factor

Abstract

AbstractHepatocyte growth factor (HGF) participates in multiple biological and pathogenic processes, such as liver regeneration, wound healing, and tumor metastasis. These biological effects are initiated by its binding to Met, so it is anticipated that compounds that can disturb the HGF‐Met association could become novel modulating drugs targeting HGF and its related signaling. In this study, a chemical library composed of 154,118 compounds was screened by in silico structure‐based drug screening (SBDS) techniques to obtain HGF‐targeting compound. X‐ray structural data of the N‐terminal and first kringle domains of HGF (PDBid: 5CS9) were analyzed using the binding energy of known inhibitors and false positive inhibitors. The top five candidate compounds, identified by the DOCK‐GOLD combined screening program, were subjected to cell‐based ELISA assay to confirm experimentally these inhibitory activity on Met activation. The present in silico SBDS study enabled identification of compound which inhibits HGF‐promoted Met phosphorylation (compound 2). The present study also suggested that Trp188/Tyr198 in HGF are essential for compound 2 binding as well as Met activation.