Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

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

Back
Research Article

In silico De Novo Discovery of Novel Target-specific Drug-like Bidentate Inhibitors of PTP 1B

Author(s): Shalini Jaswal, Kankan Roy, Priya Bisht, Priyadarshi Gautam and Sant Kumar Verma*

Volume 21, Issue 4, 2024

Published on: 08 February, 2023

Page: [763 - 781] Pages: 19

DOI: 10.2174/1570180820666230119163630

Price: $65

Abstract

Background: Protein tyrosine phosphatase 1B (PTP 1B) is a recognized legitimate target for type 2 diabetes and obesity, collectively designated as ‘diabesity’, even though first-in-class inhibitor is still awaited. The main cause behind the unachieved target selectivity of investigated inhibitors is the high degree of sharing of structural homology between PTP 1B and other members of the PTP family.

Objective: The present work aimed to discover target-specific inhibitors of PTP 1B with bidentate binding features on both the allosteric and active sites.

Materials and Methods: We have implicated the amalgamated de novo designing, ADMET screening, and molecular docking simulations to discover novel drug-like allosteric inhibitors of PTP 1B. The LEA3D de novo designing platform was used to design novel thiazolidinediones (TZDs) from scratch in the core of the target on the strict constraints of defined molecular properties of drug-likeness. Molecular modelling and geometry optimization were done using the ChemOffice package. The druglikeness/ ADMET screening was performed using the TSAR package based on Lipinski’s filter. Molegro Virtual Docker (MVD) was used for the prediction of binding cavities in the target, estimation of ligandtarget binding affinities as well as mode of binding interactions.

Results and Discussion: Novel TZDs (Molecules 1-8) were de novo designed successfully as drug-like target-specific inhibitors of PTP 1B. The interaction pattern and the energy contribution of ligand (Etotal, Eintra, Epair) and target (Epair) supported that the generated TZDs showed bidentate inhibition.

Conclusion: The discovered TZDs can be developed as novel target-specific allosteric inhibitors of PTP 1B after the accomplishment of synthetic and pre-clinical interventions.

« Previous Next »
Graphical Abstract

[1]
Verma, S.K.; Yadav, Y.S.; Thareja, S. 2,4-thiazolidinediones as PTP 1B inhibitors: A mini review (2012-2018). Mini Rev. Med. Chem., 2019, 19(7), 591-598.
[http://dx.doi.org/10.2174/1389557518666181026092029] [PMID: 30968766]
[2]
Verma, S.K.; Thareja, S. Structure based comprehensive modelling, spatial fingerprints mapping and ADME screening of curcumin analogues as novel ALR2 inhibitors. PLoS One, 2017, 12(4), e0175318.
[http://dx.doi.org/10.1371/journal.pone.0175318] [PMID: 28399135]
[3]
Thareja, S.; Aggarwal, S.; Bhardwaj, T.R.; Kumar, M. Protein tyrosine phosphatase 1B inhibitors: A molecular level legitimate approach for the management of diabetes mellitus. Med. Res. Rev., 2012, 32(3), 459-517.
[http://dx.doi.org/10.1002/med.20219] [PMID: 20814956]
[4]
International Diabetes Federation, IDF Diabetes Atlas Tenth edition. 2021. Available from: https://diabetesatlas.org/idfawp/resource-files/2021/07/IDF_Atlas_10th_Edition_2021.pdf (Accessed June 30, 2022).
[5]
Thareja, S.; Verma, S.K.; Haksar, D.; Bhardwaj, T.R.; Kumar, M. Discovery of novel cinnamylidene-thiazolidinedione derivatives as PTP-1B inhibitors for the management of type 2 diabetes. RSC Advances, 2016, 6(110), 108928-108940.
[http://dx.doi.org/10.1039/C6RA24501C]
[6]
Frangioni, J.V.; Beahm, P.H.; Shifrin, V.; Jost, C.A.; Neel, B.G. The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence. Cell, 1992, 68(3), 545-560.
[http://dx.doi.org/10.1016/0092-8674(92)90190-N] [PMID: 1739967]
[7]
Mauro, L.J.; Dixon, J.E. ‘Zip codes’ direct intracellular protein tyrosine phosphatases to the correct cellular ‘address’. Trends Biochem. Sci., 1994, 19(4), 151-155.
[http://dx.doi.org/10.1016/0968-0004(94)90274-7] [PMID: 8016862]
[8]
Woodford-Thomas, T.A.; Rhodes, J.D.; Dixon, J.E. Expression of a protein tyrosine phosphatase in normal and v-src-transformed mouse 3T3 fibroblasts. J. Cell Biol., 1992, 117(2), 401-414.
[http://dx.doi.org/10.1083/jcb.117.2.401] [PMID: 1373143]
[9]
Bakke, J.; Haj, F.G. Protein-tyrosine phosphatase 1B substrates and metabolic regulation. Semin. Cell Dev. Biol., 2015, 37, 58-65.
[http://dx.doi.org/10.1016/j.semcdb.2014.09.020] [PMID: 25263014]
[10]
Johnson, T.O.; Ermolieff, J.; Jirousek, M.R. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat. Rev. Drug Discov., 2002, 1(9), 696-709.
[http://dx.doi.org/10.1038/nrd895] [PMID: 12209150]
[11]
Tonks, N.K. PTP1B: From the sidelines to the front lines! FEBS Lett., 2003, 546(1), 140-148.
[http://dx.doi.org/10.1016/S0014-5793(03)00603-3] [PMID: 12829250]
[12]
Boute, N.; Boubekeur, S.; Lacasa, D.; Issad, T. Dynamics of the interaction between the insulin receptor and protein tyrosine‐phosphatase 1B in living cells. EMBO Rep., 2003, 4(3), 313-319.
[http://dx.doi.org/10.1038/sj.embor.embor767] [PMID: 12634852]
[13]
Dadke, S.; Kusari, J.; Chernoff, J. Down-regulation of insulin signaling by protein-tyrosine phosphatase 1B is mediated by an N-terminal binding region. J. Biol. Chem., 2000, 275(31), 23642-23647.
[http://dx.doi.org/10.1074/jbc.M001063200] [PMID: 10807907]
[14]
Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish, W.; Collins, S.; Loy, A.L.; Normandin, D.; Cheng, A.; Himms-Hagen, J.; Chan, C.C.; Ramachandran, C.; Gresser, M.J.; Tremblay, M.L.; Kennedy, B.P. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science, 1999, 283(5407), 1544-1548.
[http://dx.doi.org/10.1126/science.283.5407.1544] [PMID: 10066179]
[15]
Haj, F.G.; Markova, B.; Klaman, L.D.; Bohmer, F.D.; Neel, B.G. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J. Biol. Chem., 2003, 278(2), 739-744.
[http://dx.doi.org/10.1074/jbc.M210194200] [PMID: 12424235]
[16]
Haj, F.G.; Verveer, P.J.; Squire, A.; Neel, B.G.; Bastiaens, P.I.H. Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science, 2002, 295(5560), 1708-1711.
[http://dx.doi.org/10.1126/science.1067566] [PMID: 11872838]
[17]
Klaman, L.D.; Boss, O.; Peroni, O.D.; Kim, J.K.; Martino, J.L.; Zabolotny, J.M.; Moghal, N.; Lubkin, M.; Kim, Y.B.; Sharpe, A.H.; Stricker-Krongrad, A.; Shulman, G.I.; Neel, B.G.; Kahn, B.B. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol. Cell. Biol., 2000, 20(15), 5479-5489.
[http://dx.doi.org/10.1128/MCB.20.15.5479-5489.2000] [PMID: 10891488]
[18]
Liu, F.; Chernoff, J. Protein tyrosine phosphatase 1B interacts with and is tyrosine phosphorylated by the epidermal growth factor receptor. Biochem. J., 1997, 327(1), 139-145.
[http://dx.doi.org/10.1042/bj3270139] [PMID: 9355745]
[19]
Romsicki, Y.; Reece, M.; Gauthier, J.Y.; Asante-Appiah, E.; Kennedy, B.P. Protein tyrosine phosphatase-1B dephosphorylation of the insulin receptor occurs in a perinuclear endosome compartment in human embryonic kidney 293 cells. J. Biol. Chem., 2004, 279(13), 12868-12875.
[http://dx.doi.org/10.1074/jbc.M309600200] [PMID: 14722096]
[20]
Pelleymounter, M.A.; Cullen, M.J.; Baker, M.B.; Hecht, R.; Winters, D.; Boone, T.; Collins, F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science, 1995, 269(5223), 540-543.
[http://dx.doi.org/10.1126/science.7624776] [PMID: 7624776]
[21]
Zhang, Y.; Proenca, R.; Maffei, M.; Barone, M.; Leopold, L.; Friedman, J.M. Positional cloning of the mouse obese gene and its human homologue. Nature, 1994, 372(6505), 425-432.
[http://dx.doi.org/10.1038/372425a0] [PMID: 7984236]
[22]
Tartaglia, L.A. The leptin receptor. J. Biol. Chem., 1997, 272(10), 6093-6096.
[http://dx.doi.org/10.1074/jbc.272.10.6093] [PMID: 9102398]
[23]
Ahima, R.S.; Osei, S.Y. Leptin signaling. Physiol. Behav., 2004, 81(2), 223-241.
[http://dx.doi.org/10.1016/j.physbeh.2004.02.014] [PMID: 15159169]
[24]
Cheng, A.; Uetani, N.; Simoncic, P.D.; Chaubey, V.P.; Lee-Loy, A.; McGlade, C.J.; Kennedy, B.P.; Tremblay, M.L. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell, 2002, 2(4), 497-503.
[http://dx.doi.org/10.1016/S1534-5807(02)00149-1] [PMID: 11970899]
[25]
Zabolotny, J.M.; Bence-Hanulec, K.K.; Stricker-Krongrad, A.; Haj, F.; Wang, Y.; Minokoshi, Y.; Kim, Y.B.; Elmquist, J.K.; Tartaglia, L.A.; Kahn, B.B.; Neel, B.G. PTP1B regulates leptin signal transduction in vivo. Dev. Cell, 2002, 2(4), 489-495.
[http://dx.doi.org/10.1016/S1534-5807(02)00148-X] [PMID: 11970898]
[26]
Wang, M.Y.; Jin, Y.Y.; Wei, H.Y.; Zhang, L.S.; Sun, S.X.; Chen, X.B.; Dong, W.L.; Xu, W.R.; Cheng, X.C.; Wang, R.L. Synthesis, biological evaluation and 3D-QSAR studies of imidazolidine-2,4-dione derivatives as novel protein tyrosine phosphatase 1B inhibitors. Eur. J. Med. Chem., 2015, 103, 91-104.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.037] [PMID: 26342135]
[27]
Verma, S.K.; Thareja, S. Formylchromone derivatives as novel and selective PTP-1B inhibitors: A drug design aspect using molecular docking-based self-organizing molecular field analysis. Med. Chem. Res., 2016, 25(7), 1433-1467.
[http://dx.doi.org/10.1007/s00044-016-1584-0]
[28]
Verma, S.K.; Rajpoot, T.; Gautam, M.K. Design of novel biphenyl-2-thioxothiazolidin-4-one derivatives as potential protein tyrosine phosphatase (PTP)-1b inhibitors using molecular docking study. Lett. Drug Des. Discov., 2016, 13(4), 295-300.
[http://dx.doi.org/10.2174/1570180812666150819002954]
[29]
Verma, S.K.; Thareja, S. Molecular docking assisted 3D-QSAR study of benzylidene-2,4-thiazolidinedione derivatives as PTP-1B inhibitors for the management of type-2 diabetes mellitus. RSC Advances, 2016, 6(40), 33857-33867.
[http://dx.doi.org/10.1039/C6RA03067J]
[30]
Douguet, D.; Munier-Lehmann, H.; Labesse, G.; Pochet, S. LEA3D: a computer-aided ligand design for structure-based drug design. J. Med. Chem., 2005, 48(7), 2457-2468.
[http://dx.doi.org/10.1021/jm0492296] [PMID: 15801836]
[31]
Douguet, D. e-LEA3D: A computational-aided drug design web server. Nucleic Acids Res., 2010, 38(Web Server), W615-W621.
[http://dx.doi.org/10.1093/nar/gkq322] [PMID: 20444867]
[32]
Banjare, L.; Verma, S.K.; Jain, A.K.; Thareja, S. Structure guided molecular docking assisted alignment dependent 3dqsar study on steroidal aromatase inhibitors (SAIs) as anti-breast cancer agents. Lett. Drug Des. Discov., 2019, 16(7), 808-817.
[http://dx.doi.org/10.2174/1570180815666181010101024]
[33]
Banjare, L.; Verma, S.K.; Jain, A.K.; Thareja, S. Lead molecules as novel aromatase inhibitors: In silico de novo designing and binding affinity studies. Lett. Drug Des. Discov., 2020, 17(5), 655-665.
[http://dx.doi.org/10.2174/1570180816666190703152659]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy