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Identifying potential PPARγ agonist/partial agonist from plant molecules to control type 2 diabetes using in silico and in vivo models

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Abstract

Agonists/partial agonists of peroxisome proliferators-activated receptor gamma (PPARγ) are used in controlling type 2 diabetes mellitus (T2DM). We have identified a PPARγ agonist/partial agonist from traditional Indian medicinal plants for controlling T2DM using in silico and in vivo models. Molecular modeling and docking approaches were used in this study to identify potential plant compounds that suitably bound with PPARγ. Well-docked complex structures developed from molecular docking analysis were carefully chosen by molinspiration bioavailability and docking energy levels. Based on these results, the best docking poses were produced from the ligand-binding domain and their binding affinity was confirmed. Consequently, the plant molecule nymphayol was retrieved as a final candidate. Nymphayol was also studied for its effect on oral glucose tolerance, lipid profile, aminotransferases levels, and transcript level of PPARγ using in vivo biochemical analysis. Nymphayol showed well-docked complex with ARG 288 on ligand-binding domain of PPARγ (PDB ID: 2PRG). In molecular study, nymphayol has significantly increased PPARγ mRNA expression in adipose tissue compared to the diabetic control group. The effects of nymphayol on oral glucose tolerance, lipid profile, and aminotransferases level also showed significantly positive effects. These results indicated that nymphayol can be utilized as a potential candidate for developing novel partial agonist and antidiabetic drug targetting PPARγ.

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Abbreviations

T2DM:

type 2 diabetes mellitus

PPAR α, β, and γ:

peroxisome proliferators-activated receptor alpha, beta and gamma

ADME/T:

absorption, distribution, metabolism, excretion and toxicity

ADT:

AutoDockTool

PDB:

Protein Data Bank

HBD:

hydrogen bond donor

HBA:

hydrogen bond acceptor

STZ:

streptozotocin

TZDs:

thiazolidinediones

FBG:

fasting blood glucose

TC:

total cholesterol

TG:

triglycerides

FFA:

free fatty acids

OGTT:

oral glucose tolerance test

HDL:

high-density lipoprotein

LDL:

low-density lipoprotein

VLDL:

very low-density lipoprotein

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Acknowledgments

The authors gratefully acknowledge the Indian Council of Medical Research, New Delhi, for financial assistance [Ref. No. 74/10/2012-PERS (EMS)]. The authors also acknowledge the Deanship of Scientific Research at King Saud University, Riyadh, Saudi Arabia for its funding of this research through the Research Group project No. RGP-213.

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Authors and Affiliations

  1. Division of Bioinformatics, Entomology Research Institute, Loyola College, Chennai, 600034, India

    Antony Stalin & Savarimuthu Ignacimuthu

  2. Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai, 600034, India

    Santiagu Stephen Irudayaraj, Kedike Balakrishna & Veeramuthu Duraipandiyan

  3. Division of Molecular Biology, Entomology Research Institute, Loyola College, Chennai, 600034, India

    Dhandapani Ramesh Kumar

  4. Department of Botany and Microbiology, Addiriyah Chair for Environmental Studies, College of Science, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia

    Naif Abdullah Al-Dhabi & Veeramuthu Duraipandiyan

  5. Visitting Professor Programme, Deanship of Scienctific Research,College of Science, King Saud University, Riyadh, Saudi Arabia

    Savarimuthu Ignacimuthu

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  1. Antony Stalin
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  2. Santiagu Stephen Irudayaraj
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  3. Dhandapani Ramesh Kumar
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  4. Kedike Balakrishna
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  5. Savarimuthu Ignacimuthu
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  6. Naif Abdullah Al-Dhabi
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  7. Veeramuthu Duraipandiyan
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Correspondence to Savarimuthu Ignacimuthu.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Stalin, A., Stephen Irudayaraj, S., Ramesh Kumar, D. et al. Identifying potential PPARγ agonist/partial agonist from plant molecules to control type 2 diabetes using in silico and in vivo models. Med Chem Res 25, 1980–1992 (2016). https://doi.org/10.1007/s00044-016-1621-z

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