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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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Illustration to show how to generate the 25 derivative compounds from GW409544.(A) Structure of GW409544 and its three Cores: Core A (black), Core B (red), and Core C (blue). (B) Five compounds derived from GW409544 by changing Core C to C1, C2, C3, C4 and C5 respectively but fixing Core A and Core B at Core B1. Panels (C), (D), (E), and (F) each show another five compounds generated by following the similar procedure but fixing Core B at B2, B3, B4, and B5, respectively. See the text for further explanation.
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pone-0038546-g002: Illustration to show how to generate the 25 derivative compounds from GW409544.(A) Structure of GW409544 and its three Cores: Core A (black), Core B (red), and Core C (blue). (B) Five compounds derived from GW409544 by changing Core C to C1, C2, C3, C4 and C5 respectively but fixing Core A and Core B at Core B1. Panels (C), (D), (E), and (F) each show another five compounds generated by following the similar procedure but fixing Core B at B2, B3, B4, and B5, respectively. See the text for further explanation.

Mentions: Core Hopping [36] is a very powerful and cutting-edge technique for de novel drug design because it can significantly improve the binding affinity of the receptor with its ligands, e.g., GW409544 (Fig. 2) in the current study. The binding conformation thus obtained will be taken as an initial structure for further optimization by searching the fragment database to find the optimal cores that are attached to other parts of the template.


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 how to generate the 25 derivative compounds from GW409544.(A) Structure of GW409544 and its three Cores: Core A (black), Core B (red), and Core C (blue). (B) Five compounds derived from GW409544 by changing Core C to C1, C2, C3, C4 and C5 respectively but fixing Core A and Core B at Core B1. Panels (C), (D), (E), and (F) each show another five compounds generated by following the similar procedure but fixing Core B at B2, B3, B4, and B5, respectively. See the text for further explanation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038546-g002: Illustration to show how to generate the 25 derivative compounds from GW409544.(A) Structure of GW409544 and its three Cores: Core A (black), Core B (red), and Core C (blue). (B) Five compounds derived from GW409544 by changing Core C to C1, C2, C3, C4 and C5 respectively but fixing Core A and Core B at Core B1. Panels (C), (D), (E), and (F) each show another five compounds generated by following the similar procedure but fixing Core B at B2, B3, B4, and B5, respectively. See the text for further explanation.
Mentions: Core Hopping [36] is a very powerful and cutting-edge technique for de novel drug design because it can significantly improve the binding affinity of the receptor with its ligands, e.g., GW409544 (Fig. 2) in the current study. The binding conformation thus obtained will be taken as an initial structure for further optimization by searching the fragment database to find the optimal cores that are attached to other parts of the template.

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