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Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease.

Jin L, Wang R, Zhu Y, Zheng W, Han Y, Guo F, Ye FB, Li Y - Sci Rep (2015)

Bottom Line: Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment.Structural features critical for avermectin analogues to selectively bind to FXR were also revealed.Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.

ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels, and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling.

No MeSH data available.


Related in: MedlinePlus

Protetin-ligand docking of avermectin analogues in the ligand binding pocket of FXR.(a) A general chemical structure of ivermectin, abamectin and doramectin. (b–d) Left:The structure of FXR bound with ivermectin and the docking structures of the FXR docked with abamectin and doramectin in ribbon representation. Right: Schematic representation of interactions between FXR and avermectin analogues. Hydrogen bonds are indicated by arrows from proton donors to acceptors. The helix 3 of the FXR LBD is highlighted in green, the NCoR-2 motif is in brownish red.
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f7: Protetin-ligand docking of avermectin analogues in the ligand binding pocket of FXR.(a) A general chemical structure of ivermectin, abamectin and doramectin. (b–d) Left:The structure of FXR bound with ivermectin and the docking structures of the FXR docked with abamectin and doramectin in ribbon representation. Right: Schematic representation of interactions between FXR and avermectin analogues. Hydrogen bonds are indicated by arrows from proton donors to acceptors. The helix 3 of the FXR LBD is highlighted in green, the NCoR-2 motif is in brownish red.

Mentions: As shown in Fig. 7a, the only difference of the molecular structure between abamectin and ivermectin is the double bond and single bond at C22-C23. Doramectin differs to abamectin in the R1 group with a cyclohexane group. Eprinomectin differs to abamectin with an acetamide instead of hydroxyl group at C4” site. According to our previously published X-ray crystal structure (PDB ID: 4WVD)28, ivermectin anchors in the ligand binding domain (LBD) of FXR mainly by hydrophobic interactions with the lipophilic amino acid residues and two hydrogen bond interactions with the carbonyl oxygen on the main-chain of Arg264 and the amide carbonyl oxygen on the side-chain of Asn283, respectively (Fig. 7b). From the structural docking models in Fig. 7c, the double bond of abamectin at C22-C23 does not affect its binding to FXR compared with ivermectin binding. The cyclohexane group of doramectin in R1 group is in the spacious center of the ligand binding pocket, and it’s also hydrophobic similar to ivermectin, which does not affect its binding to FXR too (Fig. 7d). For eprinomectin, despite that the main part of eprinomectin matches well in the ligand binding pocket, the displaced acetamide group has several adverse effects on its binding in the hydrophobic ligand binding pocket. It increases the polarity of the ligand and the acetamide group of eprinomectin interferes with the side chain of Asn293 and Arg264, or even the whole helix3 and the loop between helix1 and helix2, leading to the disruption of the hydrogen bond with the amide carbonyl oxygen on the main-chain of Arg264. As for moxidectin, the loss of the bulky heterocycle group results in the insufficient hydrophobic interactions, which makes it difficult to fix well in the hydrophobic pocket of FXR.


Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease.

Jin L, Wang R, Zhu Y, Zheng W, Han Y, Guo F, Ye FB, Li Y - Sci Rep (2015)

Protetin-ligand docking of avermectin analogues in the ligand binding pocket of FXR.(a) A general chemical structure of ivermectin, abamectin and doramectin. (b–d) Left:The structure of FXR bound with ivermectin and the docking structures of the FXR docked with abamectin and doramectin in ribbon representation. Right: Schematic representation of interactions between FXR and avermectin analogues. Hydrogen bonds are indicated by arrows from proton donors to acceptors. The helix 3 of the FXR LBD is highlighted in green, the NCoR-2 motif is in brownish red.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664883&req=5

f7: Protetin-ligand docking of avermectin analogues in the ligand binding pocket of FXR.(a) A general chemical structure of ivermectin, abamectin and doramectin. (b–d) Left:The structure of FXR bound with ivermectin and the docking structures of the FXR docked with abamectin and doramectin in ribbon representation. Right: Schematic representation of interactions between FXR and avermectin analogues. Hydrogen bonds are indicated by arrows from proton donors to acceptors. The helix 3 of the FXR LBD is highlighted in green, the NCoR-2 motif is in brownish red.
Mentions: As shown in Fig. 7a, the only difference of the molecular structure between abamectin and ivermectin is the double bond and single bond at C22-C23. Doramectin differs to abamectin in the R1 group with a cyclohexane group. Eprinomectin differs to abamectin with an acetamide instead of hydroxyl group at C4” site. According to our previously published X-ray crystal structure (PDB ID: 4WVD)28, ivermectin anchors in the ligand binding domain (LBD) of FXR mainly by hydrophobic interactions with the lipophilic amino acid residues and two hydrogen bond interactions with the carbonyl oxygen on the main-chain of Arg264 and the amide carbonyl oxygen on the side-chain of Asn283, respectively (Fig. 7b). From the structural docking models in Fig. 7c, the double bond of abamectin at C22-C23 does not affect its binding to FXR compared with ivermectin binding. The cyclohexane group of doramectin in R1 group is in the spacious center of the ligand binding pocket, and it’s also hydrophobic similar to ivermectin, which does not affect its binding to FXR too (Fig. 7d). For eprinomectin, despite that the main part of eprinomectin matches well in the ligand binding pocket, the displaced acetamide group has several adverse effects on its binding in the hydrophobic ligand binding pocket. It increases the polarity of the ligand and the acetamide group of eprinomectin interferes with the side chain of Asn293 and Arg264, or even the whole helix3 and the loop between helix1 and helix2, leading to the disruption of the hydrogen bond with the amide carbonyl oxygen on the main-chain of Arg264. As for moxidectin, the loss of the bulky heterocycle group results in the insufficient hydrophobic interactions, which makes it difficult to fix well in the hydrophobic pocket of FXR.

Bottom Line: Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment.Structural features critical for avermectin analogues to selectively bind to FXR were also revealed.Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.

ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels, and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling.

No MeSH data available.


Related in: MedlinePlus