دورية أكاديمية
Targeting lipid-sensing nuclear receptors PPAR (α, γ, β/δ): HTVS and molecular docking/dynamics analysis of pharmacological ligands as potential pan-PPAR agonists.
العنوان: | Targeting lipid-sensing nuclear receptors PPAR (α, γ, β/δ): HTVS and molecular docking/dynamics analysis of pharmacological ligands as potential pan-PPAR agonists. |
---|---|
المؤلفون: | Mandal SK; Department of Biological Sciences, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India., Puri S; Department of Biological Sciences, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India., Kumar BK; Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India., Muzaffar-Ur-Rehman M; Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India., Sharma PK; Department of Biological Sciences, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India., Sankaranarayanan M; Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India., Deepa PR; Department of Biological Sciences, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India. deepa@pilani.bits-pilani.ac.in. |
المصدر: | Molecular diversity [Mol Divers] 2024 Jun; Vol. 28 (3), pp. 1423-1438. Date of Electronic Publication: 2023 Jun 06. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: ESCOM Science Publishers Country of Publication: Netherlands NLM ID: 9516534 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-501X (Electronic) Linking ISSN: 13811991 NLM ISO Abbreviation: Mol Divers Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Leiden, The Netherlands : ESCOM Science Publishers, c1995- |
مواضيع طبية MeSH: | Molecular Docking Simulation* , Molecular Dynamics Simulation* , Peroxisome Proliferator-Activated Receptors*/agonists , Peroxisome Proliferator-Activated Receptors*/metabolism , Peroxisome Proliferator-Activated Receptors*/chemistry, Ligands ; Humans ; Lipid Metabolism/drug effects |
مستخلص: | The global prevalence of obesity-related systemic disorders, including non-alcoholic fatty liver disease (NAFLD), and cancers are rapidly rising. Several of these disorders involve peroxisome proliferator-activated receptors (PPARs) as one of the key cell signaling pathways. PPARs are nuclear receptors that play a central role in lipid metabolism and glucose homeostasis. They can activate or suppress the genes responsible for inflammation, adipogenesis, and energy balance, making them promising therapeutic targets for treating metabolic disorders. In this study, an attempt has been made to screen novel PPAR pan-agonists from the ZINC database targeting the three PPAR family of receptors (α, γ, β/δ), using molecular docking and molecular dynamics (MD) simulations. The top scoring five ligands with strong binding affinity against all the three PPAR isoforms were eprosartan, canagliflozin, pralatrexate, sacubitril, olaparib. The ADMET analysis was performed to assess the pharmacokinetic profile of the top 5 molecules. On the basis of ADMET analysis, the top ligand was subjected to MD simulations, and compared with lanifibranor (reference PPAR pan-agonist). Comparatively, the top-scoring ligand showed better protein-ligand complex (PLC) stability with all the PPARs (α, γ, β/δ). When experimentally tested in in vitro cell culture model of NAFLD, eprosartan showed dose dependent decrease in lipid accumulation and oxidative damage. These outcomes suggest potential PPAR pan-agonist molecules for further experimental validation and pharmacological development, towards treatment of PPAR-mediated metabolic disorders. (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.) |
References: | Evans RM, Barish GD, Wang YX (2004) PPARs and the complex journey to obesity. Nat Med 10:355–361. https://doi.org/10.1038/nm1025. (PMID: 10.1038/nm102515057233) Fougerat A, Montagner A, Loiseau N et al (2020) Peroxisome proliferator-activated receptors and their novel ligands as candidates for the treatment of non-alcoholic fatty liver disease. Cells 9:1638. https://doi.org/10.3390/cells9071638. (PMID: 10.3390/cells9071638326504217408116) Wang F, Mullican SE, DiSpirito JR et al (2013) Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ. Proc Natl Acad Sci USA 110:18656–18661. https://doi.org/10.1073/pnas.1314863110. (PMID: 10.1073/pnas.1314863110241672563831974) Wang Y-X (2010) PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res 20:124–137. https://doi.org/10.1038/cr.2010.13. (PMID: 10.1038/cr.2010.1320101262) Jay M, Ren J (2007) Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and Type 2 diabetes mellitus. Curr Diabetes Rev 3:33–39. https://doi.org/10.2174/157339907779802067. (PMID: 10.2174/15733990777980206718220654) Berger JP, Akiyama TE, Meinke PT (2005) PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci 26:244–251. https://doi.org/10.1016/j.tips.2005.03.003. (PMID: 10.1016/j.tips.2005.03.00315860371) Zimmet P, Alberti G, Kaufman F et al (2007) The metabolic syndrome in children and adolescents. Lancet 369:2059–2061. https://doi.org/10.1016/S0140-6736(07)60958-1. (PMID: 10.1016/S0140-6736(07)60958-117586288) Engin A (2017) The definition and prevalence of obesity and metabolic syndrome. Adv Exp Med Biol 960:1–17. https://doi.org/10.1007/978-3-319-48382-5_1. (PMID: 10.1007/978-3-319-48382-5_128585193) Braissant O, Foufelle F, Scotto C et al (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat. Endocrinology 137:354–366. https://doi.org/10.1210/endo.137.1.8536636. (PMID: 10.1210/endo.137.1.85366368536636) Lehrke M, Lazar MA (2005) The many faces of PPARγ. Cell 123:993–999. https://doi.org/10.1016/j.cell.2005.11.026. (PMID: 10.1016/j.cell.2005.11.02616360030) Zarei M, Barroso E, Leiva R et al (2016) Heme-regulated eIF2α kinase modulates hepatic FGF21 and is activated by PPARβ/δ deficiency. Diabetes 65:3185–3199. https://doi.org/10.2337/db16-0155. (PMID: 10.2337/db16-015527486236) Zarei M, Barroso E, Palomer X et al (2018) Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease. Mol Metab 8:117–131. https://doi.org/10.1016/j.molmet.2017.12.008. (PMID: 10.1016/j.molmet.2017.12.00829289645) Belfiore A, Genua M, Malaguarnera R (2009) PPAR- γ agonists and their effects on igf-i receptor signaling: Implications for cancer. PPAR Res. https://doi.org/10.1155/2009/830501. (PMID: 10.1155/2009/830501196094532709717) Wagner N, Wagner K-D (2020) PPAR Beta/Delta and the hallmarks of cancer. Cells 9:1133. https://doi.org/10.3390/cells9051133. (PMID: 10.3390/cells9051133323754057291220) Park BH, Vogelstein B, Kinzler KW (2001) Genetic disruption of PPARδ decreases the tumorigenicity of human colon cancer cells. Proc Natl Acad Sci USA 98:2598–2603. https://doi.org/10.1073/pnas.051630998. (PMID: 10.1073/pnas.0516309981122628530184) Bajaj M, Suraamornkul S, Hardies LJ et al (2007) 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 50:1723–1731. https://doi.org/10.1007/s00125-007-0698-9. (PMID: 10.1007/s00125-007-0698-917520238) Gawrieh S, Noureddin M, Loo N, et al (2021) Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Elshazly S, Soliman E (2019) PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia/reperfusion injury. Toxicol Appl Pharmacol 362:86–94. https://doi.org/10.1016/j.taap.2018.10.022. (PMID: 10.1016/j.taap.2018.10.02230393147) Soliman E, Behairy SF, El-maraghy NN, Elshazly SM (2019) PPAR-γ agonist, pioglitazone, reduced oxidative and endoplasmic reticulum stress associated with L-NAME-induced hypertension in rats. Life Sci 239:117047. https://doi.org/10.1016/j.lfs.2019.117047. (PMID: 10.1016/j.lfs.2019.11704731730865) Abdellatif KRA, Fadaly WAA, Kamel GM et al (2019) Design, synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors. Bioorg Chem 82:86–99. https://doi.org/10.1016/j.bioorg.2018.09.034. (PMID: 10.1016/j.bioorg.2018.09.03430278282) Gastaldelli A, Sabatini S, Carli F et al (2021) PPAR-γ-induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH. Liver Int 41:2659–2670. https://doi.org/10.1111/liv.15005. (PMID: 10.1111/liv.15005342193619290929) Hasni S, Temesgen-Oyelakin Y, Davis M et al (2022) Peroxisome proliferator activated receptor-γagonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus. Ann Rheum Dis. https://doi.org/10.1136/ard-2022-222658. (PMID: 10.1136/ard-2022-22265835914929) Yousefnia S, Momenzadeh S, Seyed Forootan F et al (2018) The influence of peroxisome proliferator-activated receptor γ (PPARγ) ligands on cancer cell tumorigenicity. Gene 649:14–22. https://doi.org/10.1016/j.gene.2018.01.018. (PMID: 10.1016/j.gene.2018.01.01829369787) Zarei M, Aguilar-Recarte D, Palomer X, Vázquez-Carrera M (2021) Revealing the role of peroxisome proliferator-activated receptor β/δ in nonalcoholic fatty liver disease. Metabolism 114:154342. https://doi.org/10.1016/j.metabol.2020.154342. (PMID: 10.1016/j.metabol.2020.15434232810487) Choi KC, Lee SY, Yoo HJ et al (2007) Effect of PPAR-δ agonist on the expression of visfatin, adiponectin, and resistin in rat adipose tissue and 3T3-L1 adipocytes. Biochem Biophys Res Commun 357:62–67. https://doi.org/10.1016/j.bbrc.2007.03.114. (PMID: 10.1016/j.bbrc.2007.03.11417418807) Rachid TL, Penna-de-Carvalho A, Bringhenti I et al (2015) Fenofibrate (PPARalpha agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice. Mol Cell Endocrinol 402:86–94. https://doi.org/10.1016/j.mce.2014.12.027. (PMID: 10.1016/j.mce.2014.12.02725576856) Veiga FMS, Graus-Nunes F, Rachid TL et al (2017) Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice. Biochimie 140:106–116. https://doi.org/10.1016/j.biochi.2017.07.003. (PMID: 10.1016/j.biochi.2017.07.00328711683) Westerouen Van Meeteren MJ, Drenth JPH, Tjwa ETTL (2020) Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs 29:117–123. https://doi.org/10.1080/13543784.2020.1668375. (PMID: 10.1080/13543784.2020.166837531523999) Jain MR, Giri SR, Bhoi B et al (2018) Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int 38:1084–1094. https://doi.org/10.1111/liv.13634. (PMID: 10.1111/liv.1363429164820) Wright MB, Bortolini M, Tadayyon M, Bopst M (2014) Minireview: challenges and opportunities in development of PPAR agonists. Mol Endocrinol 28:1756–1768. https://doi.org/10.1210/me.2013-1427. (PMID: 10.1210/me.2013-1427251484565414793) A Phase 3 Study Evaluating Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With (NASH) and Fibrosis Stages F2 and F3 ( NATiV3 ) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04849728 . Accessed 14 May 2023. Boyer-Diaz Z, Aristu-Zabalza P, Andrés-Rozas M et al (2021) Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease. J Hepatol 74:1188–1199. https://doi.org/10.1016/j.jhep.2020.11.045. (PMID: 10.1016/j.jhep.2020.11.04533278455) Li X, Yu J, Wu M et al (2021) Pharmacokinetics and safety of Chiglitazar, a peroxisome proliferator-activated receptor pan-agonist, in patients < 65 and ≥ 65 years with Type 2 diabetes. Clin Pharmacol Drug Dev 10:789–796. https://doi.org/10.1002/cpdd.893. (PMID: 10.1002/cpdd.89333345463) Berman HM, Westbrook J, Feng Z et al (2000) The protein data bank. Nucleic Acids Res 28:235–242. https://doi.org/10.1093/nar/28.1.235. (PMID: 10.1093/nar/28.1.23510592235102472) Mandal SK, Kumar BK, Sharma PK et al (2022) In silico and in vitro analysis of PPAR – α / γ dual agonists: comparative evaluation of potential phytochemicals with anti-obesity drug orlistat. Comput Biol Med 147:105796. https://doi.org/10.1016/j.compbiomed.2022.105796. (PMID: 10.1016/j.compbiomed.2022.10579635809408) Schrödinger Release 2019-1: Schrödinger Suite 2019-1 Protein Preparation Wizard; Epik, Schrödinger, LLC, New York, NY (2019). Shaw DE, Grossman JP, Bank JA, et al (2014) Anton 2: Raising the bar for performance and programmability in a special-purpose molecular dynamics supercomputer. In: International conference for high performance computing, networking, storage and analysis, SC. IEEE, pp 41–53. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236. https://doi.org/10.1021/ja9621760. (PMID: 10.1021/ja9621760) Pires DEV, Blundell TL, Ascher DB (2015) pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem 58:4066–4072. https://doi.org/10.1021/acs.jmedchem.5b00104. (PMID: 10.1021/acs.jmedchem.5b00104258608344434528) Bowers KJ, Chow E, Xu H et al (2006) Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of the 2006 ACM/IEEE conference on supercomputing, SC’06, pp 84-es. Jacobson MP, Friesner RA, Xiang Z, Honig B (2002) On the role of the crystal environment in determining protein side-chain conformations. J Mol Biol 320:597–608. https://doi.org/10.1016/S0022-2836(02)00470-9. (PMID: 10.1016/S0022-2836(02)00470-912096912) Kumar V, Dhanjal JK, Kaul SC et al (2020) Withanone and caffeic acid phenethyl ester are predicted to interact with main protease (Mpro) of SARS-CoV-2 and inhibit its activity. J Biomol Struct Dyn 39:1–13. https://doi.org/10.1080/07391102.2020.1772108. (PMID: 10.1080/07391102.2020.1772108) Gu Y, Qi C, Sun X et al (2012) Arctigenin preferentially induces tumor cell death under glucose deprivation by inhibiting cellular energy metabolism. Biochem Pharmacol 84:468–476. https://doi.org/10.1016/j.bcp.2012.06.002. (PMID: 10.1016/j.bcp.2012.06.00222687625) Ikeguchi M (2004) Partial rigid-body dynamics in NPT, NPAT and NPγT ensembles for proteins and membranes. J Comput Chem 25:529–541. https://doi.org/10.1002/jcc.10402. (PMID: 10.1002/jcc.1040214735571) Stuart SJ, Zhou R, Berne BJ (1996) Molecular dynamics with multiple time scales: the selection of efficient reference system propagators. J Chem Phys 105:1426–1436. https://doi.org/10.1063/1.472005. (PMID: 10.1063/1.472005) De Leon JAD, Borges CR (2020) Evaluation of oxidative stress in biological samples using the thiobarbituric acid reactive substances assay. J Vis Exp. https://doi.org/10.3791/61122. (PMID: 10.3791/6112232744523) Han Y, Zhang J, Hu CQ et al (2019) In silico ADME and toxicity prediction of ceftazidime and its impurities. Front Pharmacol 10:434. https://doi.org/10.3389/fphar.2019.00434. (PMID: 10.3389/fphar.2019.00434310688216491819) Wei J, Ghosh AK, Sargent JL et al (2010) PPAR? Downregulation by TGF in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS ONE 5:e13778. https://doi.org/10.1371/journal.pone.0013778. (PMID: 10.1371/journal.pone.0013778210721702970611) Peters JM, Shah YM, Gonzalez FJ (2012) The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer 12:181–195. https://doi.org/10.1038/nrc3214. (PMID: 10.1038/nrc3214223182373322353) Rahman ST, Lauten WB, Khan QA et al (2002) Effects of eprosartan versus hydrochlorothiazide on markers of vascular oxidation and inflammation and blood pressure (renin-angiotensin system antagonists, oxidation, and inflammation). Am J Cardiol 89:686–690. https://doi.org/10.1016/S0002-9149(01)02340-2. (PMID: 10.1016/S0002-9149(01)02340-211897210) Schupp M, Janke J, Clasen R et al (2004) Angiotensin Type 1 receptor blockers induce peroxisome proliferator-activated receptor-γ activity. Circulation 109:2054–2057. https://doi.org/10.1161/01.CIR.0000127955.36250.65. (PMID: 10.1161/01.CIR.0000127955.36250.6515117841) Khare SG, Jena SK, Sangamwar AT et al (2017) Multicomponent pharmaceutical adducts of α-eprosartan: physicochemical properties and pharmacokinetic study. Cryst Growth Des 17:1589–1599. https://doi.org/10.1021/acs.cgd.6b01588. (PMID: 10.1021/acs.cgd.6b01588) |
فهرسة مساهمة: | Keywords: Drug repurposing; HTVS; Lipid metabolism; MD simulations; Pan-agonist; Peroxisome proliferator-activated receptors (PPARs) |
المشرفين على المادة: | 0 (Ligands) 0 (Peroxisome Proliferator-Activated Receptors) |
تواريخ الأحداث: | Date Created: 20230606 Date Completed: 20240724 Latest Revision: 20240724 |
رمز التحديث: | 20240726 |
DOI: | 10.1007/s11030-023-10666-y |
PMID: | 37280404 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1573-501X |
---|---|
DOI: | 10.1007/s11030-023-10666-y |