Discovery of potent apoptosis signal-regulating kinase 1 inhibitors via integrated computational strategy and biological evaluation.

Apoptosis signal-regulating Kinase 1 (ASK1) has been confirmed as a potential therapeutic target for the treatment of non-alcoholic steatohepatitis (NASH) disorder and the discovery of ASK1 inhibitors has attracted increasing attention. In this work, a series of in silico methods including pharmacophore screening, docking binding site analysis, protein-ligand interaction fingerprint (PLIF) similarity investigation and molecular docking were applied to find the potential hits from commercial compound databases. Five compounds with potential inhibitory activity were purchased and submitted to biological activity validation. Thus, one hit compound was discovered with micromolar IC50 value (10.59 μM) against ASK1. Results demonstrated that the integration of computation methods and biological test was quite reliable for the discovery of potent ASK1 inhibitors and the strategy could be extended to other similar targets of interest.