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

Future Med Chem. 2021 Feb;13(4):341-361. doi: 10.4155/fmc-2020-0253. Epub 2021 Jan 11.

Abstract

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.

Keywords: ULK1 inhibitors; autophagy; pharmacophore; structure-based Glide docking approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy-Related Protein-1 Homolog / antagonists & inhibitors*
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Evaluation, Preclinical
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ligands
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Autophagy-Related Protein-1 Homolog
  • ULK1 protein, human