Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

In Silico ADMET and Docking Studies of Thiazolidinedione-acetic-acid Hybrids as Antidiabetics with Cardioprotection

Author(s): Deepanwita Maji, Subir Samanta and Vaishali M. Patil*

Volume 17, Issue 12, 2020

Page: [1475 - 1484] Pages: 10

DOI: 10.2174/1570180817999200618103328

Price: $65

Abstract

Background: Type-2-diabetes mellitus is associated with many side effects affecting vital body organs, especially heart. Thiazolidinediones are potent antidiabetics. Studies have proven that amino-acids and peptides promote glucose transport, have antioxidant properties, and fewer side effects, thus we designed hybrids by combining amino-acid esters and peptide esters with 2, 4 thiazolidinedione acetic acid moiety which can act as antidiabetic agent with cardioprotection properties.

Methodology: In vitro ADME, toxicity, and docking studies were performed using Qikprop3.1.OSIRIS, PROTOX (Prediction of Rodent Oral Toxicity), and FlexX 2.1.3, respectively.

Results: All the designed molecules belong to three sub-series, i.e. 2, 4-dioxothiazolidine-5-acetic acid single amino acid hybrid methyl esters, 2, 4-dioxothiazolidine-5-acetic acid dipeptide hybrid methyl esters and 2, 4-dioxothiazolidine-5-acetic acid tripeptide hybrid methyl esters. All molecules were non-toxic. SSMA2, SSMA14, SSMA49, and SSDM50 showed good docking scores in 2PRG and 2UV4, respectively.

Conclusion: The selected in silico studies helped to design hybrids with less toxicity, target specificity with dual activity as potential anti-diabetic and cardioprotective agents.

Keywords: Type 2 diabetes, cardioprotection, toxicity studies, ADME, OSIRIS, ProTox, docking, flexX.

« Previous Next »
Graphical Abstract

[1]
Edition, I.D.A.S. International Diabetes Federation 2013. Update., 2014.
[2]
Fowler, M.J. Microvascular and macrovascular complications of diabetes. Clin. Diabetes, 2011, 29, 116-122.
[http://dx.doi.org/10.2337/diaclin.29.3.116]
[3]
Abushouk, A.I.; El-Husseny, M.W.A.; Bahbah, E.I.; Elmaraezy, A.; Ali, A.A.; Ashraf, A.; Abdel-Daim, M.M. Peroxisome proliferator-activated receptors as therapeutic targets for heart failure. Biomed. Pharmacother., 2017, 95, 692-700.
[http://dx.doi.org/10.1016/j.biopha.2017.08.083] [PMID: 28886529]
[4]
Oikonomou, E.; Mourouzis, K.; Fountoulakis, P.; Papamikroulis, G.A.; Siasos, G.; Antonopoulos, A.; Vogiatzi, G.; Tsalamadris, S.; Vavuranakis, M.; Tousoulis, D. Interrelationship between diabetes mellitus and heart failure: the role of peroxisome proliferator-activated receptors in left ventricle performance. Heart Fail. Rev., 2018, 23(3), 389-408.
[http://dx.doi.org/10.1007/s10741-018-9682-3] [PMID: 29453696]
[5]
Gruzman, A.; Babai, G.; Sasson, S. Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a new target for antidiabetic drugs: A review on metabolic, pharmacological and chemical considerations. Rev. Diabet. Stud., 2009, 6(1), 13-36.
[http://dx.doi.org/10.1900/RDS.2009.6.13] [PMID: 19557293]
[6]
Viollet, B.; Lantier, L.; Devin-Leclerc, J.; Hebrard, S.; Amouyal, C.; Mounier, R.; Foretz, M.; Andreelli, F. Targeting the AMPK pathway for the treatment of Type 2 diabetes. Front. Biosci., 2009, 14, 3380-3400.
[http://dx.doi.org/10.2741/3460] [PMID: 19273282]
[7]
Driver, C.; Hayangah, J.A.; Nyane, N.A.; Owira, P.M.O. Metformin with insulin relieves oxidative stress and confers renoprotection in type 1 diabetes in vivo. J. Nephropathol., 2018, 7, 171-181.
[http://dx.doi.org/10.15171/jnp.2018.37]
[8]
Sulochana, K.N.; Ge, R. Developing antiangiogenic peptide drugs for angiogenesis-related diseases. Curr. Pharm. Des., 2007, 13(20), 2074-2086.
[http://dx.doi.org/10.2174/138161207781039715] [PMID: 17627540]
[9]
Marya, K.H.; Khan, H.; Nabavi, S.M.; Habtemariam, S. Anti-diabetic potential of peptides: Future prospects as therapeutic agents. Life Sci., 2018, 193, 153-158.
[http://dx.doi.org/10.1016/j.lfs.2017.10.025] [PMID: 29055800]
[10]
Irwin, N.; Pathak, V.; Flatt, P.R. A novel CCK-8/GLP-1 hybrid peptide exhibiting prominent insulinotropic, glucose-lowering, and satiety actions with significant therapeutic potential in high-fat-fed mice. Diabetes, 2015, 64(8), 2996-3009.
[http://dx.doi.org/10.2337/db15-0220] [PMID: 25883113]
[11]
Ayeleso, A.; Joseph, J.; Belay, Y.; Kinfe, H.; Mazibuko, S.; Oguntibeju, O.; Mukwevho, E. Hybrid compounds from thiosemicarbazone and triazole as antidiabetic agents and their antioxidant potentials. Biomed. Res. (Aligarh), 2017, 28, 411-420.
[12]
Kumar, B.R.; Soni, M.; Kumar, S.S.; Singh, K.; Patil, M.; Baig, R.B.; Adhikary, L. Synthesis, glucose uptake activity and structure-activity relationships of some novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties via two carbon acyl linker. Eur. J. Med. Chem., 2011, 46(3), 835-844.
[http://dx.doi.org/10.1016/j.ejmech.2010.12.019] [PMID: 21277051]
[13]
Meng, X-Y.; Zhang, H-X.; Mezei, M.; Cui, M. Molecular docking: A powerful approach for structure-based drug discovery. Curr. Comput. Aided. Drug Des., 2011, 7(2), 146-157.
[http://dx.doi.org/10.2174/157340911795677602] [PMID: 21534921]
[14]
Mills, N. ChemDraw Ultra 10.0. J. Am. Chem. Soc., 2006, 128(41), 13649-13650.
[http://dx.doi.org/10.1021/ja0697875]
[15]
BioSolveIT GmbH. 2019.www.biosolveit.de/FlexX
[16]
QikProp; Schrödinger, LLC: New York, NY, 2019.
[17]
www.rcsb.org/pdb
[18]
Hoffer, L.; Horvath, D. S4MPLE--sampler for multiple protein-ligand entities: Simultaneous docking of several entities. J. Chem. Inf. Model., 2013, 53(1), 88-102.
[http://dx.doi.org/10.1021/ci300495r] [PMID: 23215156]
[19]
Ruiz-Ramírez, A.; Ortiz-Balderas, E.; Cardozo-Saldaña, G.; Diaz-Diaz, E.; El-Hafidi, M. Glycine restores glutathione and protects against oxidative stress in vascular tissue from sucrose-fed rats. Clin. Sci. (Lond.), 2014, 126(1), 19-29.
[http://dx.doi.org/10.1042/CS20130164] [PMID: 23742196]
[20]
McCarty, M.F.; DiNicolantonio, J.J. The cardiometabolic benefits of glycine: Is glycine an ‘antidote’ to dietary fructose? Open Heart, 2014, 1(1)e000103
[http://dx.doi.org/10.1136/openhrt-2014-000103] [PMID: 25332814]
[21]
Kim, E-D.; Kim, E.; Lee, J-H.; Hyun, C-K. Gly-Ala-Gly-Val-Gly-Tyr, a novel synthetic peptide, improves glucose transport and exerts beneficial lipid metabolic effects in 3T3-L1 adipoctyes. Eur. J. Pharmacol., 2011, 650(1), 479-485.
[http://dx.doi.org/10.1016/j.ejphar.2010.10.006] [PMID: 20951125]
[22]
Alvarado-Vásquez, N.; Zamudio, P.; Cerón, E.; Vanda, B.; Zenteno, E.; Carvajal-Sandoval, G. Effect of glycine in streptozotocin-induced diabetic rats. Comp. Biochem. Physiol. C Toxicol. Pharmacol., 2003, 134(4), 521-527.
[http://dx.doi.org/10.1016/S1532-0456(03)00046-2] [PMID: 12727302]
[23]
Alvarado-Vásquez, N.; Lascurain, R.; Cerón, E.; Vanda, B.; Carvajal-Sandoval, G.; Tapia, A.; Guevara, J.; Montaño, L.F.; Zenteno, E. Oral glycine administration attenuates diabetic complications in streptozotocin-induced diabetic rats. Life Sci., 2006, 79(3), 225-232.
[http://dx.doi.org/10.1016/j.lfs.2005.12.055] [PMID: 16483611]
[24]
Sekhar, R.V.; McKay, S.V.; Patel, S.G.; Guthikonda, A.P.; Reddy, V.T.; Balasubramanyam, A.; Jahoor, F. Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care, 2011, 34(1), 162-167.
[http://dx.doi.org/10.2337/dc10-1006] [PMID: 20929994]
[25]
Schrödinger, L.L.C. Ligprep v.2.2; Schrödinger, LLC, New York, 2008. b
[26]
Patil, V.M. R, G.K.; Chudayeu, M.; Gupta, S.P.; Samanta, S.; Masand, N.; Kaushik-Basu, N. Synthesis, in vitro and in silico NS5B polymerase inhibitory activity of benzimidazole derivatives. Med. Chem., 2012, 8(4), 629-635.
[http://dx.doi.org/10.2174/157340612801216120] [PMID: 22530910]
[27]
Patil, V.M.; Gupta, S.P.; Samanta, S.; Masand, N. Virtual screening of imidazole analogs as potential hepatitis C virus NS5B polymerase inhibitors. Chem. Pap., 2013, 67(2), 236-244.
[http://dx.doi.org/10.2478/s11696-012-0241-4]
[28]
Patil, V.M.; Masand, N.; Gurukumar, K.R.; Chudayeu, M.; Gupta, S.P.; Samanta, S.; Kaushik-Basu, N. Synthesis, in vitro and in silico NS5B polymerase inhibitory activity of benzimidazole derivatives. Anti-infective Agents. Med. Chem., 2017, 15, 52-56.
[29]
Hevener, K.E.; Zhao, W.; Ball, D.M.; Babaoglu, K.; Qi, J.; White, S.W.; Lee, R.E. Validation of molecular docking programs for virtual screening against dihydropteroate synthase. J. Chem. Inf. Model., 2009, 49(2), 444-460.
[http://dx.doi.org/10.1021/ci800293n] [PMID: 19434845]
[30]
Brooijmans, N. Docking methods, ligand design, and validating data sets in the structural genomic era. Structural Bioinformatics; John Wiley and Sons Inc.: United States, 2009, pp. 635-663.
[31]
Sander, T. OSIRIS property explorer, 2001.
[32]
Huang, N.; Shoichet, B.K.; Irwin, J.J. Benchmarking sets for molecular docking. J. Med. Chem., 2006, 49(23), 6789-6801.
[http://dx.doi.org/10.1021/jm0608356] [PMID: 17154509]
[33]

[http://dx.doi.org/tox.charite.de/tox/]
[34]
Kadam, S. Globally harmonized system of classification and labeling of chemicals. Chem. Engg. World, 2010, 45, 46-49.
[35]
Rajasekhar, K.; Surur, A.S.; Mekonnen, Y.T.; Padmavathamma, M.; Ranganayakulu, D.; Shankarananth, V. In silico prediction of biological activity, selected pharmacokinetic and toxicity profile of some 2, 4, 6-trisubstituted pyrimidines derived from Guanabenz and Guanfacine. Int. J. Innovat. Pharm. Res., 2015, 6, 468-477.
[36]
Craik, D.J.; Fairlie, D.P.; Liras, S.; Price, D. The future of peptide-based drugs. Chem. Biol. Drug Des., 2013, 81(1), 136-147.
[http://dx.doi.org/10.1111/cbdd.12055] [PMID: 23253135]
[37]
Ghosh, R.; Thanawala, V.; Kadam, V.J. Novel peptides: An alternative approach for the treatment of Diabetes mellitus. Curr. Drug Ther., 2007, 2, 196-204.
[http://dx.doi.org/10.2174/157488507781695658]
[38]
Drwal, M.N.; Banerjee, P.; Dunkel, M.; Wettig, M.R.; Preissner, R. ProTox: A web server for the in silico prediction of rodent oral toxicity. Nucleic Acids Res., 2014, 42(Web Server issue), W53-W58.
[http://dx.doi.org/10.1093/nar/gku401 ] [PMID: 24838562]
[39]
Redfern, W.S.; Carlsson, L.; Davis, A.S.; Lynch, W.G.; MacKenzie, I.; Palethorpe, S.; Siegl, P.K.; Strang, I.; Sullivan, A.T.; Wallis, R.; Camm, A.J.; Hammond, T.G. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development. Cardiovasc. Res., 2003, 58(1), 32-45.
[http://dx.doi.org/10.1016/S0008-6363(02)00846-5] [PMID: 12667944]
[40]
Babcock, J.J.; Li, M. hERG channel function: Beyond long QT. Acta Pharmacol. Sin., 2013, 34(3), 329-335.
[http://dx.doi.org/10.1038/aps.2013.6] [PMID: 23459091]
[41]
Mannhold, R.; Kubinyi, H.; Folkers, G.; Vaz, R.; Klabunde, T. Antitargets: Prediction and prevention of drug side effects; John Wiley & Sons, 2008.
[42]
Bruno, B.J.; Miller, G.D.; Lim, C.S. Basics and recent advances in peptide and protein drug delivery. Ther. Deliv., 2013, 4(11), 1443-1467.
[http://dx.doi.org/10.4155/tde.13.104] [PMID: 24228993]
[43]
Di, L. Strategic approaches to optimizing peptide ADME properties. AAPS J., 2015, 17(1), 134-143.
[http://dx.doi.org/10.1208/s12248-014-9687-3] [PMID: 25366889]
[44]
Zhong, X.; Li, X.; Qian, L.; Xu, Y.; Lu, Y.; Zhang, J.; Li, N.; Zhu, X.; Ben, J.; Yang, Q.; Chen, Q. Glycine attenuates myocardial ischemia-reperfusion injury by inhibiting myocardial apoptosis in rats. J. Biomed. Res., 2012, 26(5), 346-354.
[http://dx.doi.org/10.7555/JBR.26.20110124] [PMID: 23554770]
[45]
Nadtochiy, S.M.; Burwell, L.S.; Brookes, P.S. Cardioprotection and mitochondrial S-nitrosation: effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia-reperfusion injury. J. Mol. Cell. Cardiol., 2007, 42(4), 812-825.
[http://dx.doi.org/10.1016/j.yjmcc.2007.01.010] [PMID: 17350035]
[46]
Li, W.; Zhang, Y.; Shao, N. Protective effect of glycine in streptozotocin-induced diabetic cataract through aldose reductase inhibitory activity. Biomed. Pharmacother., 2019, 114108794
[http://dx.doi.org/10.1016/j.biopha.2019.108794] [PMID: 30947017]
[47]
Maji, D.; Samanta, S. Novel thiazolidinedione-5-acetic-acid-peptide hybrid derivatives as potent antidiabetic and cardioprotective agents. Biomed. Pharmacother., 2017, 88, 1163-1172.
[http://dx.doi.org/10.1016/j.biopha.2017.01.160]

Rights & Permissions Print Cite
Article Metrics
20
1
© 2024 Bentham Science Publishers | Privacy Policy