title: Molecular recognition between pancreatic lipase and natural and synthetic inhibitors.
abstract: Pancreatic lipase (PL) is a primary lipase critical for triacylglyceride digestion in humans and is considered as a promising target for the treatment of obesity. Although the current synthetic drugs available for treating obesity have been demonstrated to be effective in inhibiting PL, their prolonged usage results in severe side effects. Based on this argument, in this study, we evaluated the structural and energetic features linked to molecular recognition between two well-known PL inhibitors, orlistat (ORL, synthetic inhibitor) and (-)-epigallocatechin gallate (EGCG, natural inhibitor) and PL through molecular dynamics simulations and free energy calculations of ORL and EGCG at the PL binding site when it is isolated (PL) from the heterodimer complex, forming the heterodimer complex with colipase (PLCL) and lacking structural calcium. Our study showed that the binding free energy of ORL and EGCG to the target correlates with their experimental affinity tendency. The presence of the heterodimer PLCL state, the presence of structural calcium and the type of inhibitor resulted in differences in structural stability and in the map of protein-ligand and protein-protein interactions. Overall, our results suggest that the heterodimer complex and structural calcium are linked to the binding properties of PL.
authors.affiliation: Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Mirón S/N, Col. Casco de Santo Tomas, México City, CP: 11340, Mexico. Electronic address: bellomartini@gmail.com.
authors.forename: Martiniano
authors.initials: M
authors.lastname: Bello
authors.affiliation: Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Mirón S/N, Col. Casco de Santo Tomas, México City, CP: 11340, Mexico.
authors.forename: Lucia
authors.initials: L
authors.lastname: Basilio-Antonio
authors.affiliation: Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Mirón S/N, Col. Casco de Santo Tomas, México City, CP: 11340, Mexico.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fragoso-Vázquez
authors.affiliation: Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Mirón S/N, Col. Casco de Santo Tomas, México City, CP: 11340, Mexico.
authors.forename: Anaguiven
authors.initials: A
authors.lastname: Avalos-Soriano
authors.affiliation: Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Mirón S/N, Col. Casco de Santo Tomas, México City, CP: 11340, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
mesh_terms: D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000737:chemistry* / Q000627:therapeutic use; D008024:Ligands; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009765:Obesity / Q000188:drug therapy*; D000077403:Orlistat; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D008024:Ligands; D002392:Catechin; D000077403:Orlistat; C045651:epigallocatechin gallate; D008049:Lipase
keywords: (−)-epigallocatechin gallate; Binding free energy calculations; Colipase; Molecular dynamics simulations; Orlistat; Pancreatic lipase