In vivo, in vitro, and molecular docking study of rat pancreatic lipase inhibition using isopropyl salicylate

Pancreatic lipase (PL) represents a significant treatment target that has been the focus of research on anti-obesity medications. Orlistat is the only regularly used prescription that has been approved for long-term use. The discovery of new compounds for anti-obesity treatment based on PL inhibition can be achieved, in particular, by structure-based virtual screening with docking software. The aim of this research was to study isopropyl salicylate (IPS) anti-hyperlipidemic activity and inhibitory effect on rat pancreatic PL in comparison with orlistat. Wistar rats were divided into four groups of 8 animals each: control; fed with a high-fat diet (HFD) for 12 weeks to produce hyperlipidemia; fed with HFD and Orlistat (10 mg/kg BW daily); fed with HFD and IPS (10.81 mg/kg BW daily). It was shown that BW gain and lipase activity in the plasma of the high-fat diet rats treated with either orlistat or isopropyl salicylate were reduced considerably compared with untreated rats. The pancreatic lipase was partially purified from the plasma of obese rats, and a kinetic study of the IPS effect identified a competitive inhibition mode with an assessed Ki of 30.53 mM. An in silico study of the interaction between IPS and rat pancreatic lipase-related protein 2 (PDB ID: 1BU8) was conducted. The binding energy value ΔG for the IPS-protein complex at the enzyme’s active site was found to be -5.4 kcal/mol, while that for the orlistat-protein complex was -4.4 kcal/mol, indicating the stronger interaction of the enzyme with isopropyl salicylate than with orlistat. Keywords: in silico study, inhibition, isopropyl salicylate, obesity, orlistat, pancreatic lipase, rat pancreatic lipase-related protein 2