HESPERETIN DERIVATIVES AS PPAR γ AGONIST: A PHARMACOPHORE APPROACH
DOI:
https://doi.org/10.22159/ijap.2024v16i5.51538Keywords:
Hesperetin derivatives, PPAR γ agonists, Thiazolidinediones (TZDs), Molecular docking, MOL 297Abstract
Objective: The study focuses on enhancing the pharmacological activity of hesperetin, a bioflavonoid, to develop novel derivatives with improved efficacy and reduced side effects compared to existing Thiazolidinediones (TZDs) as PPAR g agonist.
Methods: The Methodology involves various computational approaches, including pharmacophore modelling, molecular docking, Molecular Mechanics with Generalised Born and Surface Area Solvation (MMGBSA), and molecular dynamics simulations. Pharmacophore modelling identifies essential binding features validated by Quantitative Structure-Activity Relationship (QSAR) models. Database screening and docking confirm lead compounds' binding affinity, with MMGBSA aiding lead optimization. Toxicological assessment ensures drug likeness and bioavailability. Molecular dynamics simulations explore protein-ligand complex stability and dynamics, revealing insights into their interactions.
Results: The results indicate MOL-297 exhibits improved properties over hesperetin, including ADME properties, solubility, blood-brain barrier permeability, docking score, and binding energy. Molecular dynamics simulations confirm Mol-297-PPAR γ complex stability, with favourable ligand-amino acid interactions.
Conclusion: The developed new molecule MOL 297, is a novel Peroxisome Proliferator-Activated Receptor (PPAR) gamma agonists with enhanced pharmacological properties, warranting further experimental validation and drug development.
Downloads
References
Bajaj M, Suraamornkul S, Hardies LJ, Glass L, Musi N, DeFronzo RA. Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus. Diabetologia. 2007;50(8):1723-31. doi: 10.1007/s00125-007-0698-9, PMID 17520238.
Chen Y, Jimenez AR, Medh JD. Identification and regulation of novel PPAR gamma splice variants in human THP-1 macrophages. Biochim Biophys Acta. 2006;1759(1-2):32-43. doi: 10.1016/j.bbaexp.2006.01.005, PMID 16542739.
Bogazzi F, Ultimieri F, Raggi F, Russo D, Manetti L, Cosci C. Abnormal expression of PPAR gamma isoforms in the subcutaneous adipose tissue of patients with cushings disease. Clin Endocrinol (Oxf). 2007;66(1):7-12. doi: 10.1111/j.1365-2265.2006.02675.x, PMID 17201795.
Gilde AJ, Van Bilsen M. Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand. 2003;178(4):425-34. doi: 10.1046/j.1365-201X.2003.01161.x, PMID 12864748.
Vidal Puig A, Jimenez Linan M, Lowell BB, Hamann A, Hu E, Spiegelman B. Regulation of PPAR γ gene expression by nutrition and obesity in rodents. J Clin Invest. 1996;97(11):2553-61. doi: 10.1172/JCI118703, PMID 8647948.
Hu W, Jiang C, Kim M, Xiao Y, Richter HJ, Guan D. Isoform-specific functions of PPARγ in gene regulation and metabolism. Genes Dev. 2022;36(5-6):300-12. doi: 10.1101/gad.349232.121, PMID 35273075.
Wagner N, Wagner KD. The role of PPARs in disease. Cells. 2020;9(11):236. doi: 10.3390/cells9112367, PMID 33126411.
Thangavel N, Al Bratty M, Akhtar Javed S, Ahsan W, Alhazmi HA. Targeting peroxisome proliferator-activated receptors using thiazolidinediones: strategy for design of novel antidiabetic drugs. Int J Med Chem. 2017;2017:1069718. doi: 10.1155/2017/1069718, PMID 28656106.
Dumasia R, Eagle KA, Kline Rogers E, May N, Cho L, Mukherjee D. Role of PPAR-γ agonist thiazolidinediones in treatment of pre-diabetic and diabetic individuals: a cardiovascular perspective. Curr Drug Targets Cardiovasc Haematol Disord. 2005;5(5):377-86. doi: 10.2174/156800605774370362, PMID 16248830.
Botta M, Audano M, Sahebkar A, Sirtori CR, Mitro N, Ruscica M. PPAR agonists and metabolic syndrome: an established role. Int J Mol Sci. 2018;19(4):1197. doi: 10.3390/ijms19041197, PMID 29662003.
Kumar AP, PP, Kumar BR, Jeyarani V, Dhanabal SP, Justin A. Glitazones PPAR-γ and neuroprotection. Mini Rev Med Chem. 2021;21(12):1457-64. doi: 10.2174/1389557521666210304112403, PMID 33663364.
Lopez JG. Flavonoids in health and disease. Curr Med Chem. 2019;26(39):6972-5. doi: 10.2174/092986732639191213095405, PMID 31920188.
Banjarnahor SD, Artanti N. Antioxidant properties of flavonoids. Med J Indones. 2014;23(4):239-44. doi: 10.13181/mji.v23i4.1015.
Pietta PG. Flavonoids as antioxidants. J Nat Prod. 2000;63(7):1035-42. doi: 10.1021/np9904509, PMID 10924197.
Ullah A, Munir S, Badshah SL, Khan N, Ghani L, Poulson BG. Important flavonoids and their role as a therapeutic agent. Molecules. 2020;25(22):5243. doi: 10.3390/molecules25225243, PMID 33187049.
Lee MA, Tan L, Yang H, Im YG, Im YJ. Structures of PPARγ complexed with lobe-glitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs. Sci Rep. 2017;7(1):16837. doi: 10.1038/s41598-017-17082-x, PMID 29203903.
Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature. 1998;395(6698):137-43. doi: 10.1038/25931, PMID 9744270.
Zieleniak A, Wojcik M, Wozniak LA. Structure and physiological functions of the human peroxisome proliferator-activated receptor γ. Arch Immunol Ther Exp (Warsz). 2008;56(5):331-45. doi: 10.1007/s00005-008-0037-y, PMID 18836859.
Schrodinger LL. Schrodinger release 2021-1: protein preparation wizard. Epic Impact Prime Schrodinger. LLC, New York; 2021.
Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT. Glide: a new approach for rapid accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004;47(7):1750-9. doi: 10.1021/jm030644s, PMID 15027866.
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT. Glide: a new approach for rapid accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739-49. doi: 10.1021/jm0306430, PMID 15027865.
Zheng Y, Zhang YL, Li Z, Shi W, Ji YR, Guo YH. Design and synthesis of 7-O-1,2,3-triazole hesperetin derivatives to relieve inflammation of acute liver injury in mice. Eur J Med Chem. 2021;213:113162. doi: 10.1016/j.ejmech.2021.113162, PMID 33493826.
Zhong G, Shen J, Chen Z, Lin Z, Long L, Wu J. Antioxidant and antitumor activities of newly synthesized hesperetin derivatives. Molecules. 2022;27(3):879. doi: 10.3390/molecules27030879, PMID 35164142.
Mistry B, Patel RV, Keum YS. Access to the substituted benzyl-1,2,3-triazolyl hesperetin derivatives expressing antioxidant and anticancer effects. Arab J Chem. 2017;10(2):157-66. doi: 10.1016/j.arabjc.2015.10.004.
Ding HW, Huang AL, Zhang YL, Li B, Huang C, Ma TT. Design synthesis and biological evaluation of hesperetin derivatives as potent anti-inflammatory agent. Fitoterapia. 2017;121:212-22. doi: 10.1016/j.fitote.2017.07.016, PMID 28774689.
Jung KY, Park J, Han YS, Lee YH, Shin SY, Lim Y. Synthesis and biological evaluation of hesperetin derivatives as agents inducing apoptosis. Bioorg Med Chem. 2017;25(1):397-407. doi: 10.1016/j.bmc.2016.11.006, PMID 27840137.
Schrodinger 2022-1. Small molecule drug discovery. Portland: Schrodinger LLC; 2022.
Darshit BS, Balaji B, Rani P, Ramanathan M. Identification and in vitro evaluation of new leads as selective and competitive glycogen synthase kinase-3β inhibitors through ligand and structure-based drug design. J Mol Graph Model. 2014;53:31-47. doi: 10.1016/j.jmgm.2014.06.013, PMID 25064440.
Kinarivala N, Suh JH, Botros M, Webb P, Trippier PC. Pharmacophore elucidation of phosphoiodyn a Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity. Bioorg Med Chem Lett. 2016;26(8):1889-93. doi: 10.1016/j.bmcl.2016.03.028, PMID 26988304.
Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA. PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. methodology and preliminary results. J Comput Aided Mol Des. 2006;20(10-11):647-71. doi: 10.1007/s10822-006-9087-6, PMID 17124629.
Faris A, Ibrahim IM, Hadni H, Elhallaoui M. High throughput virtual screening of phenylpyrimidine derivatives as selective JAK3 antagonists using computational methods. J Biomol Struct Dyn. 2024;42(14):7574-99. doi: 10.1080/07391102.2023.2240413.
Research DES. Desmond molecular dynamics system. New York: Schrodinger Release; 2019.
Zhou Z, Felts AK, Friesner RA, Levy RM. Comparative performance of several flexible docking programs and scoring functions: enrichment studies for a diverse set of pharmaceutically relevant targets. J Chem Inf Model. 2007;47(4):1599-608. doi: 10.1021/ci7000346, PMID 17585856.
Kumar AP, Mandal S, PP, Faizan S, Kumar BR, Dhanabal SP. Rational design molecular docking dynamic simulation synthesis PPAR-γ competitive binding and transcription analysis of novel glitazones. J Mol Struct. 2022;1265(5):133354. doi: 10.1016/j.molstruc.2022.133354.
Schrodinger, QikProp LL. New York, Vol. 2015; 2021.
Djajadisastra J, Purnama HD, Yanuar A. In silico binding interaction study of mefenamic acid and piroxicam on human albumin. Int J App Pharm. 2017;9(10):56-62. doi: 10.22159/ijap.2017.v9s1.56_62.
Mahfudin U, Subarnas A, Wilar G, Hermanto F. Potential activity of kaempferol as antiparkinson; molecular docking and pharmacophore modelling study. Int J App Pharm. 2023;15(3):43-8. doi: 10.22159/ijap.2023v15i3.47355.
Hermanto F, Syam AK, Haq FA, Rachmawan RL. Structure-based drug design method: molecular docking study and pharmacophore modelling of apigenin as an antimalarial. Int J App Pharm. 2023;15(3):272-7. doi: 10.22159/ijap.2023v15i3.47487.
Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017 Jul 11;23(7):804-14. doi: 10.1038/nm.4350, PMID 28697184.
Corona JC, Duchen MR. PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease. Free Radic Biol Med. 2016 Nov;100:153-63. doi: 10.1016/j.freeradbiomed.2016.06.023, PMID 27352979.
Hussain R, Zubair H, Pursell S, Shahab M. Neurodegenerative diseases: regenerative mechanisms and novel therapeutic approaches. Brain Sci. 2018 Sep 15;8(9):177. doi: 10.3390/brainsci8090177.
Pizcueta P, Vergara C, Emanuele M, Vilalta A, Rodriguez Pascau L, Martinell M. Development of PPARγ agonists for the treatment of neuroinflammatory and neurodegenerative diseases: leriglitazone as a promising candidate. Int J Mol Sci. 2023 Feb 6;24(4):3201. doi: 10.3390/ijms24043201, PMID 36834611.
Kaserer T, Beck KR, Akram M, Odermatt A, Schuster D. Pharmacophore models and pharmacophore-based virtual screening: concepts and applications exemplified on hydroxysteroid dehydrogenases. Molecules. 2015 Dec 19;20(12):22799-832. doi: 10.3390/molecules201219880, PMID 26703541.
Published
How to Cite
Issue
Section
Copyright (c) 2024 RAMANATHAN MUTHIAH, VIJAYALAKSHMI CHINNIAH, MAIDA ENGELS. S. E.
This work is licensed under a Creative Commons Attribution 4.0 International License.
