Limits...
Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach.

Ma Y, Wang SQ, Xu WR, Wang RL, Chou KC - PLoS ONE (2012)

Bottom Line: By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes.It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates.Since the "core hopping" technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

View Article: PubMed Central - PubMed

Affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China.

ABSTRACT
Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful "core hopping" and "glide docking" techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the "core hopping" technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

Show MeSH

Related in: MedlinePlus

Illustration to show the conformation obtained by docking GW409544 and Comp#1, respectively, to (A) PPARα (1k7l) and (B) PPARγ (1k74).The binding pocket is defined by those residues that have at least one heavy atom with a distance of 5 Å from the ligand [45]. The ligand GW409544 (in grey color) was extracted from the crystal structure while the ligand Comp#1 (rendered by three colors: grey for Core A; red for Core B; and blue for Core C) was generated by the “core-hopping” method. The hydrophobic surface of the receptor is colored in green. The blue dotted lines indicate the H-bond interactions of the receptor with its ligand. The red helix is a part of AF-2 function domain. See the text for further explanation.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369836&req=5

pone-0038546-g001: Illustration to show the conformation obtained by docking GW409544 and Comp#1, respectively, to (A) PPARα (1k7l) and (B) PPARγ (1k74).The binding pocket is defined by those residues that have at least one heavy atom with a distance of 5 Å from the ligand [45]. The ligand GW409544 (in grey color) was extracted from the crystal structure while the ligand Comp#1 (rendered by three colors: grey for Core A; red for Core B; and blue for Core C) was generated by the “core-hopping” method. The hydrophobic surface of the receptor is colored in green. The blue dotted lines indicate the H-bond interactions of the receptor with its ligand. The red helix is a part of AF-2 function domain. See the text for further explanation.

Mentions: The information of the binding pocket of a receptor for its ligand is very important for drug design, particularly for conducting mutagenesis studies [14]. In the literatures, the binding pocket of a protein receptor to a ligand is usually defined by those residues that have at least one heavy atom (i.e., an atom other than hydrogen) with a distance ≤5 Å from a heavy atom of the ligand. Such a criterion was originally used to define the binding pocket of ATP in the Cdk5-Nck5a* complex [45] that has later proved quite useful in identifying functional domains and stimulating the relevant truncation experiments [46]. The similar approach has also been used to define the binding pockets of many other receptor-ligand interactions important for drug design [15], [17], [47], [48]. In this study, we also used the same criterion [45] to define the binding pockets of proteins 1k7l and 1k74 for the ligand GW409544. A close-up view for the protein-ligand interaction at the binding pocket thus defined is shown in Fig. 1, where panel A is for the interaction between PPARα (1k71) and GW409544, while panel B for the interaction between PPARγ (1k74) and GW409544.


Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach.

Ma Y, Wang SQ, Xu WR, Wang RL, Chou KC - PLoS ONE (2012)

Illustration to show the conformation obtained by docking GW409544 and Comp#1, respectively, to (A) PPARα (1k7l) and (B) PPARγ (1k74).The binding pocket is defined by those residues that have at least one heavy atom with a distance of 5 Å from the ligand [45]. The ligand GW409544 (in grey color) was extracted from the crystal structure while the ligand Comp#1 (rendered by three colors: grey for Core A; red for Core B; and blue for Core C) was generated by the “core-hopping” method. The hydrophobic surface of the receptor is colored in green. The blue dotted lines indicate the H-bond interactions of the receptor with its ligand. The red helix is a part of AF-2 function domain. See the text for further explanation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369836&req=5

pone-0038546-g001: Illustration to show the conformation obtained by docking GW409544 and Comp#1, respectively, to (A) PPARα (1k7l) and (B) PPARγ (1k74).The binding pocket is defined by those residues that have at least one heavy atom with a distance of 5 Å from the ligand [45]. The ligand GW409544 (in grey color) was extracted from the crystal structure while the ligand Comp#1 (rendered by three colors: grey for Core A; red for Core B; and blue for Core C) was generated by the “core-hopping” method. The hydrophobic surface of the receptor is colored in green. The blue dotted lines indicate the H-bond interactions of the receptor with its ligand. The red helix is a part of AF-2 function domain. See the text for further explanation.
Mentions: The information of the binding pocket of a receptor for its ligand is very important for drug design, particularly for conducting mutagenesis studies [14]. In the literatures, the binding pocket of a protein receptor to a ligand is usually defined by those residues that have at least one heavy atom (i.e., an atom other than hydrogen) with a distance ≤5 Å from a heavy atom of the ligand. Such a criterion was originally used to define the binding pocket of ATP in the Cdk5-Nck5a* complex [45] that has later proved quite useful in identifying functional domains and stimulating the relevant truncation experiments [46]. The similar approach has also been used to define the binding pockets of many other receptor-ligand interactions important for drug design [15], [17], [47], [48]. In this study, we also used the same criterion [45] to define the binding pockets of proteins 1k7l and 1k74 for the ligand GW409544. A close-up view for the protein-ligand interaction at the binding pocket thus defined is shown in Fig. 1, where panel A is for the interaction between PPARα (1k71) and GW409544, while panel B for the interaction between PPARγ (1k74) and GW409544.

Bottom Line: By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes.It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates.Since the "core hopping" technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

View Article: PubMed Central - PubMed

Affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China.

ABSTRACT
Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful "core hopping" and "glide docking" techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the "core hopping" technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

Show MeSH
Related in: MedlinePlus