TY - JOUR
T1 - Molecular recognition between pancreatic lipase and natural and synthetic inhibitors
AU - Bello, Martiniano
AU - Basilio-Antonio, Lucia
AU - Fragoso-Vázquez, Jonathan
AU - Avalos-Soriano, Anaguiven
AU - Correa-Basurto, José
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - (−)-epigallocatechin gallate
KW - Binding free energy calculations
KW - Colipase
KW - Molecular dynamics simulations
KW - Orlistat
KW - Pancreatic lipase
UR - http://www.scopus.com/inward/record.url?scp=85013344072&partnerID=8YFLogxK
U2 - 10.1016/j.ijbiomac.2017.01.150
DO - 10.1016/j.ijbiomac.2017.01.150
M3 - Artículo
C2 - 28212930
SN - 0141-8130
VL - 98
SP - 855
EP - 868
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
ER -