TY - JOUR
T1 - Structural and energetic basis for novel epicatechin derivatives acting as GPER agonists through the MMGBSA method
AU - Bello, Martiniano
AU - Méndez-Luna, David
AU - Sarmiento, Viviana
AU - Correa Basurto, José
AU - Najera, Nayelli
AU - Villarreal, Francisco
AU - Ceballos, Guillermo
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/5
Y1 - 2019/5
N2 - (-)-Epicatechin (Epi) has been demonstrated to activate pathways involved in GPER-stimulated nitric oxide (NO) production via endothelial NO synthase, known as the eNOS/NO pathway. Previous studies combining synthesis of four Epi derivatives demonstrated that Epi and Epi-prop, Epi-4-prop and Epi-5-prop were able to bind GPER by acting as GPER agonists, whereas docking studies allowed observation of structural details of the binding of these derivatives at the GPER binding site. However, due to the nature of past studies, the theoretical methods employed did not allow observation of structural and energetic details linked to ligand binding at the GPER binding site. In this contribution, we explore the structural and energetic changes coupling the binding of Epi and its four derivatives to GPER. To this end, MD simulations on the microsecond scale (1 μs) with an MMGBSA approach were used for each GPER-ligand complex. Energetic analysis demonstrated that incorporation of several aliphatic chains to Epi contributed to increasing the affinity towards the GPER binding site, thus helping to explain the experimental evidence. Structural analysis demonstrated that Epi, Epi-4-prop and Epi-5-prop share more similar interactions at GPER binding sites with similar conformational behavior than with Epi-prop and Epi-Ms. However, Epi-prop had additional residues that could explain its different but related biological effects.
AB - (-)-Epicatechin (Epi) has been demonstrated to activate pathways involved in GPER-stimulated nitric oxide (NO) production via endothelial NO synthase, known as the eNOS/NO pathway. Previous studies combining synthesis of four Epi derivatives demonstrated that Epi and Epi-prop, Epi-4-prop and Epi-5-prop were able to bind GPER by acting as GPER agonists, whereas docking studies allowed observation of structural details of the binding of these derivatives at the GPER binding site. However, due to the nature of past studies, the theoretical methods employed did not allow observation of structural and energetic details linked to ligand binding at the GPER binding site. In this contribution, we explore the structural and energetic changes coupling the binding of Epi and its four derivatives to GPER. To this end, MD simulations on the microsecond scale (1 μs) with an MMGBSA approach were used for each GPER-ligand complex. Energetic analysis demonstrated that incorporation of several aliphatic chains to Epi contributed to increasing the affinity towards the GPER binding site, thus helping to explain the experimental evidence. Structural analysis demonstrated that Epi, Epi-4-prop and Epi-5-prop share more similar interactions at GPER binding sites with similar conformational behavior than with Epi-prop and Epi-Ms. However, Epi-prop had additional residues that could explain its different but related biological effects.
KW - Epicatechin
KW - GPER
KW - MMGBSA
KW - Molecular dynamics simulations
KW - Principal component analysis
UR - http://www.scopus.com/inward/record.url?scp=85062810985&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2019.03.006
DO - 10.1016/j.jsbmb.2019.03.006
M3 - Artículo
C2 - 30851383
SN - 0960-0760
VL - 189
SP - 176
EP - 186
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
ER -