Discovery of arginine-containing tripeptides as a new class of pancreatic lipase inhibitors

Future Med Chem. 2019 Jan;11(1):5-19. doi: 10.4155/fmc-2018-0216. Epub 2018 Dec 11.

Abstract

Aim: The inhibition of pancreatic lipase (PL) represents one of the most promising strategies in the search for novel antiobesity drugs. We propose here a pioneering course by exploring tripeptide scaffolds in the way to selective PL inhibitors.

Methodology/results: The peptide series exhibited good PL inhibitory properties in vitro, with all the strongest inhibitors sharing a central arginine, shown in silico to be relevant for the active site-directed activity. The compounds were found devoid of inhibitory properties on acetylcholinesterase.

Conclusion: Present results disclosed that basic tripeptides are able to interact efficiently with the PL-binding pocket, where they adopt a binding pose suitable for functional-to-inhibition interactions with key amino acids. Main inhibitor MALA4 may be selected as lead for further optimization.

Keywords: arginine; enzyme inhibition; obesity; pancreatic lipase; tripeptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Anti-Obesity Agents / chemical synthesis*
  • Arginine / analogs & derivatives*
  • Arginine / chemistry*
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Lipase / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Docking Simulation
  • Oligopeptides / chemical synthesis*
  • Pancreas / enzymology*
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Anti-Obesity Agents
  • Cholinesterase Inhibitors
  • Enzyme Inhibitors
  • Oligopeptides
  • Arginine
  • Lipase
  • Acetylcholinesterase