research-article

Exploring fingerprints for antidiabetic therapeutics related to peroxisome proliferator-activated receptor gamma (PPARγ) modulators: : A chemometric modeling approach

Authors:

Shovanlal Gayen,

Sk Abdul AminAuthors Info & Claims

Volume 112, Issue C

https://doi.org/10.1016/j.compbiolchem.2024.108142

Published: 01 October 2024 Publication History

Abstract

This study demonstrated the correlation of molecular structures of Peroxisome proliferator-activated receptor gamma (PPARγ) modulators and their biological activities. Bayesian classification, and recursive partitioning (RP) studies have been applied to a dataset of 323 PPARγ modulators with diverse scaffolds. The results provide a deep insight into the important sub-structural features modulating PPARγ. The molecular docking analysis again confirmed the significance of the identified sub-structural features in the modulation of PPARγ activity. Molecular dynamics simulations further underscored the stability of the complexes formed by investigated modulators with PPARγ. Overall, the integration of many computational approaches unveiled key structural motifs essential for PPARγ modulatory activity that will shed light on the development of effective modulators in the future.

Graphical Abstract

Display Omitted

Highlight

•

This study focused on the supervised mathematical learning models of PPARγ modulators.

•

Exploring favorable and unfavorable sub-structural fragments that regulate PPARγ modulatory activities.

•

Molecular docking and MD simulation studies of structural fingerprints in the drug-binding pockets of PPARγ.

References

[1]

M.J. Abraham, T. Murtola, R. Schulz, S. Páll, J.C. Smith, B. Hess, E. Lindahl, GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers, SoftwareX 1 (2015) 19–25.

[2]

J.J. Acton 3rd, T.E. Akiyama, C.H. Chang, L. Colwell, S. Debenham, T. Doebber, M. Einstein, K. Liu, M.E. McCann, D.E. Moller, E.S. Muise, Y. Tan, J.R. Thompson, K.K. Wong, M. Wu, L. Xu, P.T. Meinke, J.P. Berger, H.B. Wood, Discovery of (2R)-2-(3-{3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic acid (MK-0533): a novel selective peroxisome proliferator-activated receptor gamma modulator for the treatment of type 2 diabetes mellitus with a reduced potential to increase plasma and extracellular fluid volume, J. Med. Chem. 52 (2009) 3846–3854,.

[3]

J.J. Acton 3rd, R.M. Black, A.B. Jones, D.E. Moller, L. Colwell, T.W. Doebber, K.L. Macnaul, J. Berger, H.B. Wood, Benzoyl 2-methyl indoles as selective PPARgamma modulators, Bioorg. Med. Chem. Lett. 15 (2005) 357–362,.

[4]

American Diabetes Association, Diagnosis and classification of diabetes mellitus, Diabetes Care 32 Suppl 1 (Suppl 1) (2009) S62–S67,. PMID: 19118289; PMCID: PMC2613584.

[5]

S.A. Amin, S. Nandi, S.K. Kashaw, T. Jha, S. Gayen, A critical analysis of urea transporter B inhibitors: molecular fingerprints, pharmacophore features for the development of next-generation diuretics, Mol. Divers 26 (2022) 2549–2559,.

[6]

J. Berger, D.E. Moller, The mechanisms of action of PPARs, Annu. Rev. Med. 53 (2002) 409–435,.

[7]

A. Bhattacharjee, S. Kar, P.K. Ojha, Unveiling G-protein coupled receptor kinase-5 inhibitors for chronic degenerative diseases: Multilayered prioritization employing explainable machine learning-driven multi-class QSAR, ligand-based pharmacophore and free energy-inspired molecular simulation, Int. J. Biol. Macromol. 269 (2024),.

[8]

J.B. Bruning, M.J. Chalmers, S. Prasad, S.A. Busby, T.M. Kamenecka, Y. He, K.W. Nettles, P.R. Griffin, Partial agonists activate PPARgamma using a helix 12 independent mechanism, Structure 15 (2007) 1258–1271,.

[9]

M.W. Carpenter, D.R. Coustan, Criteria for screening tests for gestational diabetes, Am. J. Obstet. Gynecol. 144 (1982) 768–773,.

[10]

F. Chiarelli, D. Di Marzio, Peroxisome proliferator-activated receptor-gamma agonists and diabetes: Current evidence and future perspectives, Vasc. Health Risk Manag. 4 (2008) 297–304,.

[11]

S.D. Debenham, A. Chan, F.W. Lau, W. Liu, H.B. Wood, K. Lemme, L. Colwell, B. Habulihaz, T.E. Akiyama, M. Einstein, T.W. Doebber, N. Sharma, C.F. Wang, M. Wu, J.P. Berger, P.T. Meinke, Highly functionalized 7-azaindoles as selective PPAR gamma modulators, Bioorg. Med. Chem. Lett. 18 (2008) 4798–4801,.

[12]

W.L. DeLano, Pymol: an open-source molecular graphics tool, CCP4 newsl, Protein Crystallogr. 40 (2002) (2002) 82–92.

[13]

R.C. Desai, D.F. Gratale, W. Han, H. Koyama, E. Metzger, V.K. Lombardo, K.L. MacNaul, T.W. Doebber, J.P. Berger, K. Leung, R. Franklin, D.E. Moller, J.V. Heck, S.P. Sahoo, Aryloxazolidinediones: Identification of potent orally active PPAR dual alpha/gamma agonists, Bioorg. Med. Chem. Lett. 13 (2003) 3541–3544,.

[14]

R.C. Desai, W. Han, E.J. Metzger, J.P. Bergman, D.F. Gratale, K.L. MacNaul, J.P. Berger, T.W. Doebber, K. Leung, D.E. Moller, J.V. Heck, S.P. Sahoo, 5-aryl thiazolidine-2,4-diones: discovery of PPAR dual alpha/gamma agonists as antidiabetic agents, Bioorg. Med. Chem. Lett. 13 (2003) 2795–2798,.

[15]

R.C. Desai, E. Metzger, C. Santini, P.T. Meinke, J.V. Heck, J.P. Berger, K.L. MacNaul, T.Q. Cai, S.D. Wright, A. Agrawal, D.E. Moller, S.P. Sahoo, Design and synthesis of potent and subtype-selective PPARalpha agonists, Bioorg. Med. Chem. Lett. 16 (2006) 1673–1678,.

[16]

Discovery Studio 3.0 (DS 3.0), Accelrys Inc., CA, USA, 2015. Available at www.accelrys.com.

[17]

J.F. Dropinski, T. Akiyama, M. Einstein, B. Habulihaz, T. Doebber, J.P. Berger, P.T. Meinke, G.Q. Shi, Synthesis and biological activities of novel aryl indole-2-carboxylic acid analogs as PPARgamma partial agonists, Bioorg. Med. Chem. Lett. 15 (2005) 5035–5038,.

[18]

T. Fawcett, An introduction to ROC analysis, Pattern Recognit. Lett. 27 (2006) 861–874,.

Digital Library

[19]

R.L. Frkic, K. Richter, J.B. Bruning, The therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 diabetes, J. Biol. Chem. 297 (2021),.

[20]

B. Gross, B. Staels, PPAR agonists: multimodal drugs for the treatment of type-2 diabetes, Best. Pract. Res Clin. Endocrinol. Metab. 21 (2007) 687–710,.

[21]

B. Grygiel-Górniak, Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review, Nutr. J. 13 (2014) 17,.

[22]

M. Hernandez-Quiles, M.F. Broekema, E. Kalkhoven, PPARgamma in metabolism, immunity, and cancer: Unified and diverse mechanisms of action, Front Endocrinol. (Lausanne) 12 (2021),.

[23]

B. Hess, C. Holm, N. van der Vegt, Osmotic coefficients of atomistic NaCl (aq) force fields, J. Chem. Phys. 124 (2006) doi.org/10.1063/1.2185105.

[24]

M.A. Jay, J. Ren, Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus, Curr. Diabetes Rev. 3 (2007) 33–39,.

[25]

S. Jo, T. Kim, V.G. Iyer, W. Im, CHARMM-GUI: a web-based graphical user interface for CHARMM, J. Comput. Chem. 29 (2008) 1859–1865. doi.org/10.1002/jcc.20945.

[26]

L.P. Kagami, G.M. das Neves, L.F.S.M. Timmers, R.A. Caceres, V.L. Eifler-Lima, Geo-Measures: a PyMOL plugin for protein structure ensembles analysis, Comput. Biol. Chem. 87 (2020),.

[27]

H. Koyama, J.K. Boueres, W. Han, E.J. Metzger, J.P. Bergman, D.F. Gratale, D.J. Miller, R.L. Tolman, K.L. MacNaul, J.P. Berger, T.W. Doebber, K. Leung, D.E. Moller, J.V. Heck, S.P. Sahoo, 5-Aryl thiazolidine-2,4-diones as selective PPARgamma agonists, Bioorg. Med. Chem. Lett. 13 (2003) 1801–1804,.

[28]

H. Koyama, J.K. Boueres, D.J. Miller, J.P. Berger, K.L. MacNaul, P.R. Wang, M.C. Ippolito, S.D. Wright, A.K. Agrawal, D.E. Moller, S.P. Sahoo, 2R)-2-methylchromane-2-carboxylic acids: discovery of selective PPARalpha agonists as hypolipidemic agents, Bioorg. Med. Chem. Lett. 15 (2005) 3347–3351,.

[29]

H. Koyama, D.J. Miller, J.K. Boueres, R.C. Desai, A.B. Jones, J.P. Berger, K.L. MacNaul, L.J. Kelly, T.W. Doebber, M.S. Wu, G. Zhou, P.R. Wang, M.C. Ippolito, Y.S. Chao, A.K. Agrawal, R. Franklin, J.V. Heck, S.D. Wright, D.E. Moller, S.P. Sahoo, 2R)-2-ethylchromane-2-carboxylic acids: discovery of novel PPARalpha/gamma dual agonists as antihyperglycemic and hypolipidemic agents, J. Med. Chem. 47 (2004) 3255–3263,.

[30]

J. Lee, X. Cheng, S. Jo, A.D. MacKerell, J.B. Klauda, W. Im, CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field, Biophys. J. 110 (2016) 641a. doi.org/10.1021/acs.jctc.5b00935.

[31]

K. Liu, R.M. Black, J.J. Acton 3rd, R. Mosley, S. Debenham, R. Abola, M. Yang, R. Tschirret-Guth, L. Colwell, C. Liu, M. Wu, C.F. Wang, K.L. MacNaul, M.E. McCann, D.E. Moller, J.P. Berger, P.T. Meinke, A.B. Jones, H.B. Wood, Selective PPARgamma modulators with improved pharmacological profiles, Bioorg. Med. Chem. Lett. 15 (2005) 2437–2440,.

[32]

W. Liu, F. Lau, K. Liu, H.B. Wood, G. Zhou, Y. Chen, Y. Li, T.E. Akiyama, G. Castriota, M. Einstein, C. Wang, M.E. McCann, T.W. Doebber, M. Wu, C.H. Chang, L. McNamara, B. McKeever, R.T. Mosley, J.P. Berger, P.T. Meinke, Benzimidazolones: A new class of selective peroxisome proliferator-activated receptor γ (PPARγ) modulators, J. Med. Chem. 54 (2011) 8541–8554,.

[33]

W. Liu, K. Liu, H.B. Wood, M.E. McCann, T.W. Doebber, C.H. Chang, T.E. Akiyama, M. Einstein, J.P. Berger, P.T. Meinke, Discovery of a peroxisome proliferator activated receptor gamma (PPARgamma) modulator with balanced PPARalpha activity for the treatment of type 2 diabetes and dyslipidemia, J. Med. Chem. 52 (2009) 4443–4453,.

[34]

K. Liu, L. Xu, J.P. Berger, K.L. Macnaul, G. Zhou, T.W. Doebber, M.J. Forrest, D.E. Moller, A.B. Jones, Discovery of a novel series of peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes and dyslipidemia, J. Med. Chem. 48 (2005) 2262–2265,.

[35]

M. Moinul, S.A. Amin, P. Kumar, U.K. Patil, A. Gajbhiye, T. Jha, S. Gayen, Exploring sodium glucose cotransporter (SGLT2) inhibitors with machine learning approach: A novel hope in anti-diabetes drug discovery, J. Mol. Graph. Model. 111 (2022),.

[36]

S. Nandi, P. Kumar, S.A. Amin, T. Jha, S. Gayen, First molecular modelling report on tri-substituted pyrazolines as phosphodiesterase 5 (PDE5) inhibitors through classical and machine learning based multi-QSAR analysis, SAR QSAR Environ. Res. 32 (2021) 917–939,.

[37]

N.M. O'Boyle, M. Banck, C.A. James, C. Morley, T. Vandermeersch, G.R. Hutchison, Open Babel: an open chemical toolbox, J. Chemin.-. 3 (2011) 1–4. doi.org/10.1186/1758-2946-3-33.

[38]

E.F. Pettersen, T.D. Goddard, C.C. Huang, G.S. Couch, D.M. Greenblatt, E.C. Meng, T.E. Ferrin, UCSF Chimera—a visualization system for exploratory research and analysis., J. Comput. Chem. 13 (2004) 1605–1612. doi.org/10.1002/jcc.20084.

[39]

S.M. Rangwala, M.A. Lazar, Peroxisome proliferator-activated receptor gamma in diabetes and metabolism, Trends Pharmacol. Sci. 25 (2004) 331–336,.

[40]

C. Santini, G.D. Berger, W. Han, R. Mosley, K. MacNaul, J. Berger, T. Doebber, M. Wu, D.E. Moller, R.L. Tolman, S.P. Sahoo, Phenylacetic acid derivatives as hPPAR agonists, Bioorg. Med. Chem. Lett. 13 (2003) 1277–1280,.

[41]

M.T. Sheehan, Current therapeutic options in type 2 diabetes mellitus: a practical approach, Clin. Med. Res. 1 (2003) 189–200,.

[42]

G.Q. Shi, J.F. Dropinski, B.M. McKeever, S. Xu, J.W. Becker, J.P. Berger, K.L. MacNaul, A. Elbrecht, G. Zhou, T.W. Doebber, P. Wang, Y.S. Chao, M. Forrest, J.V. Heck, D.E. Moller, A.B. Jones, Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity, J. Med. Chem. 48 (2005) 4457–4468,.

[43]

G.Q. Shi, J.F. Dropinski, Y. Zhang, C. Santini, S.P. Sahoo, J.P. Berger, K.L. Macnaul, G. Zhou, A. Agrawal, R. Alvaro, T.Q. Cai, M. Hernandez, S.D. Wright, D.E. Moller, J.V. Heck, P.T. Meinke, Novel 2,3-dihydrobenzofuran-2-carboxylic acids: highly potent and subtype-selective PPARalpha agonists with potent hypolipidemic activity, J. Med. Chem. 48 (2005) 5589–5599,.

[44]

J.W. Szewczyk, S. Huang, J. Chin, J. Tian, L. Mitnaul, R.L. Rosa, L. Peterson, C.P. Sparrow, A.D. Adams, SAR studies: designing potent and selective LXR agonists, Bioorg. Med. Chem. Lett. 16 (2006) 3055–3060,.

[45]

O. Trott, A.J. Olson, AutoDockVina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J. Comput. Chem. 31 (2010) 455–461,.

[46]

G. Wilcox, Insulin and insulin resistance, Clin. Biochem. Rev. 26 (2005) 19–39.

[47]

T.M. Willson, P.J. Brown, D.D. Sternbach, B.R. Henke, The PPARs: From orphan receptors to drug discovery, J. Med. Chem. 43 (2000) 527–550,.

[48]

C.W. Yap, PaDEL-descriptor: an open source software to calculate molecular descriptors and fingerprints, J. Comput. Chem. 32 (2011) 1466–1474,.

Index Terms

Exploring fingerprints for antidiabetic therapeutics related to peroxisome proliferator-activated receptor gamma (PPARγ) modulators: A chemometric modeling approach
1. Applied computing
  1. Life and medical sciences
2. Computing methodologies
  1. Machine learning
    1. Learning paradigms
      1. Supervised learning

Index terms have been assigned to the content through auto-classification.

Recommendations

Antidiabetic potency and molecular insights of natural products bearing indole moiety: A systematic bioinformatics investigation targeting AKT1
Abstract
Diabetic mellitus (DM) is a chronic disorder, and type 2 DM (T2DM) is the most prevalent among all categories (nearly 90%) across the globe every year. With the availability of potential drugs, the prevalence rate has remained uncontrollable, ...
Graphical Abstract

Display Omitted
Highlights
- Therapeutic repurposing of natural indole-derivatives.
- Anti-diabetic potency of plant and marine derived indoles.
- Computational platform to select potential antidiabetic candidates.
A multidrug efflux protein in Mycobacterium tuberculosis; tap as a potential drug target for drug repurposing
Abstract
Tuberculosis (TB) is a serious communicative disease caused by Mycobacterium tuberculosis. Although there are vaccines and drugs available to treat the disease, they are not efficient, moreover, multidrug-resistant ...
Graphical abstract

Display Omitted
Highlights
- Tuberculosis (TB) is a serious communicative disease caused by M. tuberculosis.
Computational analysis of natural compounds as potential phosphodiesterase type 5A inhibitors
Abstract
Phosphodiesterase type 5 (PDE5) is a cyclic nucleotide-hydrolyzing enzyme that plays essential roles in the regulation of second messenger cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) produced in response to ...
Graphical Abstract

Display Omitted

Comments

Please enable JavaScript to view thecomments powered by Disqus.

Information & Contributors

Information

Published In

cover image Computational Biology and Chemistry

Computational Biology and Chemistry Volume 112, Issue C

Oct 2024

820 pages

Issue’s Table of Contents

Elsevier Ltd.

Publisher

Elsevier Science Publishers B. V.

Netherlands

Publication History

Published: 01 October 2024

Author Tags

Qualifiers

Research-article

Contributors

Other Metrics

View Article Metrics

Bibliometrics & Citations

Bibliometrics

Article Metrics

0
Total Citations
0
Total Downloads

Downloads (Last 12 months)0
Downloads (Last 6 weeks)0

Reflects downloads up to 05 Mar 2025

Other Metrics

View Author Metrics

Citations

View Options

View options

Figures

Tables

Media

View Issue’s Table of Contents