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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.

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Related in: MedlinePlus

Illustration to show the outcomes of molecular dynamics simulations for Comp#1 ranked number 1 in Table 1.(A) The RMSD (root mean square deviation) of all backbone atoms for the receptor PPARα. (B) The RMSF (root mean square fluctuation) of the side-chain atoms for the receptor PPARα. (C) The RMSD (root mean square deviation) of all backbone atoms for the receptor PPARγ. (D) The RMSF (root mean square fluctuation) of the side-chain atoms for the receptor PPARγ. The green line indicates the outcome for the system of the receptor alone without any ligand, the red line for that of the receptor with the ligand GW409544, and the black line for that of the receptor with the ligand Comp#1. The curves involved with the AF2 helix region are framed with grey line. See the text for further explanation.
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pone-0038546-g003: Illustration to show the outcomes of molecular dynamics simulations for Comp#1 ranked number 1 in Table 1.(A) The RMSD (root mean square deviation) of all backbone atoms for the receptor PPARα. (B) The RMSF (root mean square fluctuation) of the side-chain atoms for the receptor PPARα. (C) The RMSD (root mean square deviation) of all backbone atoms for the receptor PPARγ. (D) The RMSF (root mean square fluctuation) of the side-chain atoms for the receptor PPARγ. The green line indicates the outcome for the system of the receptor alone without any ligand, the red line for that of the receptor with the ligand GW409544, and the black line for that of the receptor with the ligand Comp#1. The curves involved with the AF2 helix region are framed with grey line. See the text for further explanation.

Mentions: Molecular dynamics can provide useful information for characterizing the internal motions of biomacromolecules with time. For a comparison study, the 10 ns molecular dynamics simulations were performed, respectively, for the crystal structures of PPARα (1k7l), PPARγ (1k74), as well as their complexes with GW409544 and Comp#1, i.e., PPARα-GW409544, PPARγ-GW409544, PPARα-Comp#1, and PPARγ-Comp#1. As we can see from Fig. 3, all the characters concerned reached the simulation equilibrium within the 5ns (see panels A and C).


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 outcomes of molecular dynamics simulations for Comp#1 ranked number 1 in Table 1.(A) The RMSD (root mean square deviation) of all backbone atoms for the receptor PPARα. (B) The RMSF (root mean square fluctuation) of the side-chain atoms for the receptor PPARα. (C) The RMSD (root mean square deviation) of all backbone atoms for the receptor PPARγ. (D) The RMSF (root mean square fluctuation) of the side-chain atoms for the receptor PPARγ. The green line indicates the outcome for the system of the receptor alone without any ligand, the red line for that of the receptor with the ligand GW409544, and the black line for that of the receptor with the ligand Comp#1. The curves involved with the AF2 helix region are framed with grey line. See the text for further explanation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038546-g003: Illustration to show the outcomes of molecular dynamics simulations for Comp#1 ranked number 1 in Table 1.(A) The RMSD (root mean square deviation) of all backbone atoms for the receptor PPARα. (B) The RMSF (root mean square fluctuation) of the side-chain atoms for the receptor PPARα. (C) The RMSD (root mean square deviation) of all backbone atoms for the receptor PPARγ. (D) The RMSF (root mean square fluctuation) of the side-chain atoms for the receptor PPARγ. The green line indicates the outcome for the system of the receptor alone without any ligand, the red line for that of the receptor with the ligand GW409544, and the black line for that of the receptor with the ligand Comp#1. The curves involved with the AF2 helix region are framed with grey line. See the text for further explanation.
Mentions: Molecular dynamics can provide useful information for characterizing the internal motions of biomacromolecules with time. For a comparison study, the 10 ns molecular dynamics simulations were performed, respectively, for the crystal structures of PPARα (1k7l), PPARγ (1k74), as well as their complexes with GW409544 and Comp#1, i.e., PPARα-GW409544, PPARγ-GW409544, PPARα-Comp#1, and PPARγ-Comp#1. As we can see from Fig. 3, all the characters concerned reached the simulation equilibrium within the 5ns (see panels A and C).

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