TY - JOUR
T1 - Structural basis of Nrf2 activation by flavonolignans from silymarin
AU - Bello, Martiniano
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2023/3
Y1 - 2023/3
N2 - Several properties of silymarin (SM) extract have been attributed to their three major flavonolignans (silybin, silychristin, and silydianin) and their 2,3-dehydro derivatives (2,3-dehydrosilybin, 2,3-dehydrosilychristin, and 2,3-dehydrosilydianin). Experimental findings have suggested that the antioxidative and protective activities of these compounds could be due to their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2). The mechanism by which SM compounds exert their effect has been suggested to be by disrupting the complex between Nrf2 and Kelch-like ECH-associated protein 1 (Keap1). However, information about the structural and energetic basis of the inhibitory mechanism of SM compounds on the Nrf2-Keap1 pathway is lacking. We evaluated the binding properties of SM compounds because experimental findings have pointed to them as potential activators of Nrf2. Our study combined docking and molecular dynamics (MD) simulations with the Poisson–Boltzmann and generalized Born and surface area (MMPBSA and MMGBSA) methods and quantum mechanics-molecular mechanics (QMMM) calculations to investigate Keap1–ligand interactions. Our results predicted that silybinA and 2,3-dehydrosilybin bind to Keap1, forming interactions with the same pockets as those observed for the cocrystallized Keap1-Cpd16 complex but with more favorable binding free energies. These findings indicate that both natural compounds are potential activators of Nrf2.
AB - Several properties of silymarin (SM) extract have been attributed to their three major flavonolignans (silybin, silychristin, and silydianin) and their 2,3-dehydro derivatives (2,3-dehydrosilybin, 2,3-dehydrosilychristin, and 2,3-dehydrosilydianin). Experimental findings have suggested that the antioxidative and protective activities of these compounds could be due to their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2). The mechanism by which SM compounds exert their effect has been suggested to be by disrupting the complex between Nrf2 and Kelch-like ECH-associated protein 1 (Keap1). However, information about the structural and energetic basis of the inhibitory mechanism of SM compounds on the Nrf2-Keap1 pathway is lacking. We evaluated the binding properties of SM compounds because experimental findings have pointed to them as potential activators of Nrf2. Our study combined docking and molecular dynamics (MD) simulations with the Poisson–Boltzmann and generalized Born and surface area (MMPBSA and MMGBSA) methods and quantum mechanics-molecular mechanics (QMMM) calculations to investigate Keap1–ligand interactions. Our results predicted that silybinA and 2,3-dehydrosilybin bind to Keap1, forming interactions with the same pockets as those observed for the cocrystallized Keap1-Cpd16 complex but with more favorable binding free energies. These findings indicate that both natural compounds are potential activators of Nrf2.
KW - Docking
KW - Keap1
KW - MD simulations
KW - MMGBSA
KW - Nrf2
UR - http://www.scopus.com/inward/record.url?scp=85144031146&partnerID=8YFLogxK
U2 - 10.1016/j.jmgm.2022.108393
DO - 10.1016/j.jmgm.2022.108393
M3 - Artículo
C2 - 36525840
AN - SCOPUS:85144031146
SN - 1093-3263
VL - 119
JO - Journal of Molecular Graphics and Modelling
JF - Journal of Molecular Graphics and Modelling
M1 - 108393
ER -