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

Published: 21 November 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.

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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,.
[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,.

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    Information & Contributors

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    Published In

    cover image Computational Biology and Chemistry
    Computational Biology and Chemistry  Volume 112, Issue C
    Oct 2024
    820 pages

    Publisher

    Elsevier Science Publishers B. V.

    Netherlands

    Publication History

    Published: 21 November 2024

    Author Tags

    1. Diabetes mellitus
    2. PPARγ modulators
    3. Recursive partitioning
    4. Molecular docking
    5. MD simulation
    6. Fingerprint

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