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O-linked-N- acetyl glucosaminetransferase (OGT) is an important enzyme which regulates many important cellular processes through posttranscriptional modification of the nuclear and cytosolic proteins. OGT catalyzes the attachment of N- acetylglucosamine portion of uridine diphosphate N- acetyl glucosamine (UDP- GlcNac) to the serine and threonine residues of nuclear and cytoplasmic proteins of multicellular eukaryote in protein O-GlcNacylation process. Hyperglycemia increases GlcNacylation of proteins. GlcNacylation has been linked to some human diseases, such as cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, and cancer. Several inhibitors of the enzyme have been explored in the treatment of the diseases associated with it. In this study, alkaloids were mined from online database and screened computationally using molecular docking approach. 290 alkaloids were retrieved and docked against OGT, using OGT complexed with a thio – linked substrate as the control, and the docking approach predicted 14-norpseurotinA (14-NSA), Protoveratrine B (PB) and 3-(4-methoxyphenyl)-3-[[2-(4-methoxyphenyl)-1-oxoethyl] amino] propanoic acid (MPOAPA) to be suitable inhibitors of OGT, through their interaction and binding pose with the amino acid residues at the substrate-binding site of the protein, with a docking score of -11.106, -9.176 and -8.269 respectively. Additionally, the hit compounds were then subjected to ADMETox screening to predict their drug – likeness. The ADMETox analysis predicted that 14-NSA, and MPOAPA shows more drug-like characteristics compared to PB and the co crystallised ligand by obeying the rule of five for drug development. However, natural bioactive compounds 14-NSA, and MPOAPA could be a potential active site inhibitor of OGT in the treatment of cancer, diabetes, neurodegenerative diseases and cardiovascular diseases caused by aberrant O- GlcNacylation.
Hahne H. et al. Proteome wide purification and identification of O-GlcNAc-modified proteins using click chemistry and mass spectrometry. Journal of Proteome Research. 2013;12:927–936.
Holt GD, Snow CM, Senior A, Haltiwanger RS, Gerace L, Hart GW. J. Cell Biol. 1987; 104:1157–1164.
Olivier-Van Stichelen S, Drougat L, Dehennaut V, El Yazidi-Belkoura I, Guinez C, Mir AM, Michalski JC, Vercoutter-Edouart AS and T. Lefebvre, Oncogenesis; 2012.
Drougat L, Olivier-Van Stichelen S, Mortuaire M, Foulquier F, Lacoste AS, Michalski JC, Lefebvre T, Vercoutter-Edouart AS. Biochim. Biophys. Acta, 2012; 1820:1839–1848.
Li MD, Ruan HB, Hughes M, Lee JS, Singh J, Jones S, Nitabach M, Yang X. Cell Metab. 2013;17:303–310.
Zachara NE, Hart GW. O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress. Biochim. Biophys. Acta. 2004;1673:13–28.
Iyer SP, Hart GW, Dynamic nuclear and cytoplasmic glycosylation: enzymes of O-GlcNAc cycling, Biochemistry. 2003;42:2493–2499.
Lubas WA, Frank DW, Krause M, Hanover JA. O-linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J. Biol. Chem. 1997; 272(14):9316 24.
Jinek M, Rehwinkel J, Lazarus BD, Izaurralde E, Hanover JA, Conti E. Nat. Struct. Mol. Biol. 2004;11:1001–1007.
McClain DA, Lubas WA, Cooksey, RC, Hazel M, Parker GJ, Love DC, Hanover JA. Altered glycan-dependent signalling induces insulin resistance and hyperleptinemia. Proceedings of the National Academy of Sciences. 2002; 99(16):10695-10699.
Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O. Cross-talk between O-GlcNAcylation and phosphorylation: roles in signalling, transcription, and chronic disease. Annual Review of Biochemistry. 2011; 80:825-858.
Love DC, Hanover JA. The hexosamine signalling pathway: deciphering the ‘‘O GlcNAc code. Sci. STKE 2005, re13.
Zhang H, Gao G, Brunk UT. Extracellular reduction of alloxan results in oxygen radical‐mediated attack on plasma and lysosomal membranes. Apmis. 1992;100:317–325.
Ortiz-Meoz RF. et al. A small molecule that inhibits OGT activity in cells. ACS Chem. Biol. 2015;10:1392–1397.
James LR. et al. Flux Through the Hexosamine Pathway Is a Determinant of Nuclear Factor κB–Dependent Promoter Activation. Diabetes. 2002;51:1146–1156.
Trapannone R, Rafie K, van Aalten DM. O-GlcNAc transferase inhibitors: current tools and future challenges. Biochem. Soc. Trans. 2016;44:88–93.
McNaught, A. D. Compendium of chemical terminology. Oxford: Blackwell Science. 1997; 1669.
Wang S, Moustaid-Moussa N, Chen L, Mo H, Shastri A. Novel insights of dietary polyphenols and obesity. J Nutr Biochem. 2014; 25:1-18
Saeidnia S, Abdollahi M. Toxicological and pharmacological concerns on oxidative stress and related diseases. 2013; 15;273(3):442-55.
Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH. PubChem Substance and Compound databases. Nucleic Acids Research. 2016;44:D1202-D1213.
Schrodinger Release 2018-4: Lig Prep schrodinger. New York, NY: LLC, 2018.
Asthana A, Zafeiriou S, Cheng S, Pantic M. Incremental face alignment in the wild. In Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition. 2014; 1859-1866.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Bourne PE. The protein data bank. Nucleic Acids Research. 2000;28(1):235-242.2
David TI, Adelakun NS, Omotuyi OI, Metibemu DS, Ekun OE. Molecular docking analysis of Phyto-constituents from Cannabis sativa with pfDHFR. Bioinformation. 2018; 14(9):574.
Schrodinger Release: Maestro schrodinger. New York, NY: LLC, 2018;8-4:201.
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Shenkin PS. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry. 2004;47(7):1739-1749.
Release S. 2: Qikprop, Schrodinger; 2021.
Schrödinger Release 2021-1: Glide, Schrödinger, LLC, New York, NY; 2021.
Inyang OK, Omotuyi OI, Ogunleye AJ, Eniafe GO, Adewumi B. Molecular Interaction and Inhibitory Potential of Polyphenol on DNA Repair Pathway in Small Cell Lung Cancer: A Computational Study. J Anal Pharm Res. 2017;6.
Lipinski CA. Lead-and drug-like compounds: the rule-of-five revolution. Drug discovery today: Technologies. 2004;1(4):337-341.
Karim Rafie, Andrii Gorelik, Riccardo Trapannone, Vladimir S Borodkin, Daan MF. Aalten. Thio-linked UDP-peptide conjugates as O-GlcNAc transferase inhibitors. Bioconjugate Chem. 2018;1-1-16.