Adibah Amirah Abdul Nasir*, and Ezatul Ezleen Kamarulzaman
Obesity is now become pandemic in the whole worldwide. Obesity usually caused among city people who are having sedentary lifestyles than those who live in countryside. In Southeast Asia, Malaysia has the highest population of people having obesity in ASEAN region (1). Obesity is one of metabolic disorder diseases, which occurred because of imbalance between energy intakes (4). A body mass index greater than 30 kg/m2 is classified as overweight or obese. Obesity problems usually associated with many chronic diseases such as cardiovascular disease, diabetes type II, arteriosclerosis, and stroke. Orlistat is a known anti-obesity drug, which has been proved to give lowering weight effect by 35 percent reduction in dietary fats absorption (9).
A study on the human pancreatic lipase (PDB ID: 1LPB) is the most well studied protein for therapeutics of obesity via inhibition of pancreatic lipase (5,6,7). The main role of pancreatic lipase is to hydrolyze the dietary fat into fatty acids and glycerides to be able absorbed into small intestine. Therefore, by reducing fat absorption via pancreatic lipase inhibition, obesity can be reduced and treated.
Studies on natural products especially plants give a huge contribution towards drug discovery today (2). Many plant extracts such as Prunella vulgaris, Achyrantes aspera, Plumbago zeylanica and Rheum palmatum have been tested through in vivo and in vitro studies and showed that chemical constituents of these plants exhibit anti-obesity activity by increasing thermogenesis, increasing fat metabolism, suppressing food intake, and retard fat absorption via pancreatic lipase inhibition. (3,4,8).
Experimental and results
In silico study was carried out on selected plants to find the lead compounds that can inhibit pancreatic lipase. Malaysian ethno botanical plants that have potential in reducing body weight were selected to be the candidates of pancreatic lipase inhibitors. The chemical structures of the plants were taken from NADI database (www.nadi-discovery.com). The three dimensional structure of pancreatic lipase was obtained from Protein Data Bank (PDB ID: 1LPB) with its inhibitor, MUP. Hydrogen atoms were added to the protein. MUP ligand was re-docked into the active pocket of the macromolecule with 50 x 50 x 60 in grid points in x, y, and z coordinates. The RMSD value for control docking is 1.14 Å. Therefore, parameters used for control docking can be further utilized in virtual screening of pancreatic lipase inhibitor.
Figure 1. Three-dimensional structure of 1LPB with the catalytic triad
The docking results showed that five plants associated with its chemical compounds showing lower free energy binding such as 13-cis-beta-carotene from Anacardium occidentale (-13.52 kcal/mol), phyllocladene from Syzgium aromaticum (-9.22 kcal/mol), morinthone from Morinda citrofolia (-9.58 kcal/mol), stigmasterol from Punica granatum (-12.3 kcal/mol), and 3-beta-25-Dihydroxy-5-beta-19-epoxycucurbita-6,(23E)-diene from Momordica charantia (-11.78 kcal/mol). Docked ligands have formed molecular interactions with residues Ala178, Leu153, Phe77, Tyr114, Ser152 and Phe215 through hydrogen bond and hydrophobic interactions.
All docking simulation and visualization works were performed by Autodock Tools version 1.5.6, AutoDock4 software and Discovery Studio 4.0, Accelrys Software Inc. respectively.
Figure 2. Five chemical compounds from selected Malaysian plants with weight reducing potential
Bioactive compounds from Anacardium occidentale, Syzgium aromaticum, Morinda citrofolia, Punica granatum, and Momordica charantia could be a good potential as lead compounds for treating obesity via pancreatic lipase inhibition.