Insight into the interaction of human pancreatic lipase with potential anti-obesity drug, Cetilistat, using a molecular docking and molecular dynamics simulation

Background: Obesity is a lifestyle disease that involves an excessive amount of body fat deposition. Cetilistat is being used to treat obesity. It mainly inhibits human pancreatic lipase, an enzyme that helps to break down the oil into small molecules of glycerol and fatty acids in the intestine. Therefore, pancreatic lipase inhibition is a potential therapeutic approach for obesity control and treatment. Methods: cetilistat’s binding mode and interaction with human pancreatic lipase are not well understood. In this study, the human pancreatic lipase inhibitory activity of cetilistat was investigated by employing molecular docking and molecular dynamics simulation. Human pancreatic lipase has two states: closed state and open state which is controlled by a surface loop i.e. “lid region” which normally undergoes conformational changes only upon addition of lipids and then breakdown into glycerol and fatty acid. In the present study, open state conformation of the human pancreatic lipase structure was used (2OXE.pdb). The docking study reveals that the cetilistat prefers to bind at the “lid region” of pancreatic lipase. Furthermore, molecular dynamics simulation reveals that the cetilistat affects the structure and dynamics of human pancreatic lipase. Mainly, cetilistat affects the conformational changes in the “lid region” of pancreatic lipase which is important for the breakdown of lipids. Furthermore, the radius of gyration (Rg) and solvent-accessible surface area shows that the cetilistat-bound pancreatic lipase affects the compactness of the lipase structure. Thus, our computational modeling study reveals the inhibitory action of cetilistat with human pancreatic lipase and may be further useful for the design and development of anti-obesity drugs. Results: To explore the binding mode and interaction of HPL with cetilistat, we employed molecular docking, a molecular dynamics simulation study. The details of which are discussed below. Conclusion: Thus, our computational modeling study reveals the inhibitory action of cetilistat with human pancreatic lipase and may be further useful for the design and development of anti-obesity drugs.