In silico approaches using pharmacophore model combined with molecular docking for discovery of novel ULK1 inhibitors.

Background: Discovery of effective autophagy-initiating kinase ULK1 inhibitors has attracted more and more attention in cancer treatment. Methodology & results: The present study describes the application of a pharmacophore-based virtual screening and structure-based docking approach guided drug design. Compound U-2 exhibited a nanomolar range of IC50 against the ULK1 target. Molecular dynamics simulation was used to assess the quality of docking studies. The determinants of binding affinity were investigated, and a different binding pattern was observed. Subsequently, prediction properties of ADMET (absorption, distribution, metabolism, excretion and toxicity) and hepatotoxicity in vitro studies indicated that U-2 possessed good drug-like properties. Moreover, western blot analysis indicated that the compound inhibited autophagic flux in cells. Conclusion: The present study provides an appropriate guideline for discovering novel ULK1 inhibitors. The novel compound may serve as a good starting point for further development and optimizations.