{"id":28714,"date":"2019-09-25T10:34:05","date_gmt":"2019-09-25T10:34:05","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=28714"},"modified":"2020-04-22T10:45:01","modified_gmt":"2020-04-22T10:45:01","slug":"in-silico-analysis-of-glycogen-synthase-kinase-3-beta-gsk-3%ce%b2-as-aflatoxin-binder","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol12no3\/in-silico-analysis-of-glycogen-synthase-kinase-3-beta-gsk-3%ce%b2-as-aflatoxin-binder\/","title":{"rendered":"In Silico Analysis of Glycogen Synthase Kinase 3-Beta (GSK-3\u03b2) As Aflatoxin Binder"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Mycotoxins are natural fungal secondary metabolites with low-molecular-weight (i.e., small molecules) produced by \ufb01lamentous fungi and the most important genera of mycotoxin-producing fungi are Aspergillus, Fusarium, Stachybotrys, Claviceps, Penicillium<\/em> and \u00a0Alternaria<\/em> (1). The principal classes of mycotoxins, which cause health problems in animals and human beings, include aflatoxin, trichothecenes, fumonisins, zearalenone and ochratoxin A (2). Aflatoxins are potent mycotoxin (fungal toxin) capable of causing death on humans and animals. There are several types of aflatoxins, among them, aflatoxins B1, B2, G1, G2, M1, and M2 are commonly studied (3). It is highly pathogenic and leads to carcinogenic, mutagenic, hepatotoxic and immunosuppressant effects in animals and humans (4\u20136). Particularly in children, it causes stunted growth, immunosuppression, liver cancer and even death; when they consume milk from dairy cattle that feed an aflatoxin contaminated feed (7,8). Moreover, a\ufb02atoxin B1 (AFB1) is the most potent carcinogenic (biological) agent which has been reported by several researchers throughout the world (9). Furthermore, in dairy cattle, after the consumption of Aflatoxin contaminated feed,\u00a0 AFB1 and AFB2 will be biotransformed into hydroxylated metabolites like a\ufb02atoxin M1 (AFM1) and M2 (AFM2) respectively; that later contaminates milk and milk products (10\u201312).<\/p>\n

Glycogen Synthase Kinase 3-beta (GSK-3\u03b2) was first identified as a negative regulator of glycogenesis and subsequently reported to regulate varies signalling pathway and cellular function. GSK-3\u03b2 is an important enzyme in the process of neurogenesis, neuronal migration, differentiation and survival of immature brain (13,14). Numerous studies have been reported for the binding ability of GSK-3\u03b2 with certain chemical compounds and plant extracts. In addition to this few potential inhibitors have been reported for this enzyme (15-16). Recently aflatoxin B1 has reported binding with GSK-3\u03b2 (17). This incited to carry out the present study, where GSK-3\u03b2 was evaluated on the docking behaviour of 13 aflatoxin analogues using Patch Dock as well as physicochemical, drug-likeness and ADME (Absorption, Distribution, Metabolism and Excretion) analyses were also carried out.<\/p>\n

Material and Methods<\/strong><\/p>\n

Ligand preparation<\/strong><\/p>\n

Thirteen types of Aflatoxins were prepared as a ligand for this study, as illustrated in Table 1. The ligands were\u00a0 namely (I) Aflatoxin B1; (II) Aflatoxin G1; (III) Aflatoxin M1; (IV) Aflatoxin B2; (V) Aflatoxin G2; (VI) Aflatoxin M2; (VII) Tetrahydrodeoxy aflatoxin B1; (VIII) Compound 2; (IX) Compound 8; (X) Compound 11; (XI) Aflatoxin Q1; (XII) Aflatoxin P1; (XIII) Aflatoxin B1-8,9-epoxide (18). The chemical structures of these thirteen Aflatoxin analogues were first drawn in ChemBio Draw Ultra 12.0 (www.cambridgesoft.com<\/em>) and subsequently the molecular mechanics (MM2) energy minimization of ligands were carried out by ChemBio 3D Ultra 12.0, according to the reported procedure (19). These minimized energy structures were further utilized for Patch Dock study.<\/p>\n

Identification and preparation of target protein <\/strong><\/p>\n

The three dimensional (3D) structure of the target protein Glycogen synthase kinase 3-beta \u00a0(GSK-3\u03b2), PDB 3F88 with resolution of 2.6 A0<\/sup> was obtained from the Research Collaborator for Structural Bioinformatics (RCSB) Protein Data Bank (www.rcsb.org<\/em>) (20). The first task was preparing the protein by removing another chains (B, C and D) on it other than the A chain, by using UCSF Chimera software (www.cgi.ucsf.edu\/chimera<\/em>), followed by removing water particles (without hydrogen bonds) which are crystallographically observed (21). Then prepared protein was uploaded to the Patch Dock server with each pre-prepared ligands for docking analysis.<\/p>\n

Molecular descriptors calculation<\/strong><\/p>\n

Smiles of our prepared ligands are then copied to an online software to calculate the thirteen descriptors by using the online database of Molinspiration (www.molinspiration.com<\/em>). The molecular descriptors studied in this study are log P, molecular weight, polar surface area, number of atoms, number of rotatable bond, number of O or N, number of OH or NH, ion channel modulator, drug-likeness including G protein coupled receptors ligand, kinase inhibitor, nuclear receptor ligand, and number of violations to Lipinski\u2019s rule (20).<\/p>\n

Analysis of ADME <\/strong><\/p>\n

ADME (Absorption, Distribution, Metabolism and Excretion) analysis was carried out \u00a0for all the 13 aflatoxin analogues using Swiss ADME. A standard default protocol was adopted for the same (20,22).<\/p>\n

Docking studies<\/strong><\/p>\n

To conduct docking studies all the ligand and protein were uploaded to an online server called PatchDock (http:\/\/bioinfo3d.cs.tau.ac.il\/PatchDock<\/em>). The docking results were sent to our pre-registered email address and all the data are obtained from it.\u00a0 Patch Dock uses geometry-based molecular docking algorithm method to recognize the binding scores, by binding residues atomic contact energy of the given ligands. The ACE and other information are copied and the first solution selected from the top of lists of several solutions (the docked protein-ligand complex) and downloaded in a database (pdb) file format. Finally, analysis\u00a0 of the protein for having a binding site for the Aflatoxin analogues \u00a0were done by PyMOL software (www.pymol.org), by opening and measuring the bond distance and also identification and labelling the amino acids which binds with the particular ligand \u00a0(20,21).<\/p>\n

Results and Discussion<\/strong><\/p>\n

Aflatoxins are potent mycotoxins which are now threatening both the feed and livestock sector throughout the world. In recent years\u2019, numbers of aflatoxin binders have been reported in the literature (23). For instance, few commercial available aflatoxin binders are aflabalan, astra-ben-20, anzymit, flow guard, formycin, mycoflix plus, mycosorb, red crown and SA-20 (24\u201326). Thus, in the present study Glycogen synthase kinase 3-beta (GSK-3\u03b2) was evaluated on the docking behaviour of 13 aflatoxin analogues using PatchDock. Table 1 represents the thirteen ligands structure and SMILES selected for the present study.<\/p>\n\n\n\n
\"Table<\/td>\nTable 1: Thirteen aflatoxin analogues selected for the present study<\/strong><\/p>\n

Click here to view table<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Note: *- (I) Aflatoxin B1; (II) Aflatoxin G1; (III) Aflatoxin M1; (IV) Aflatoxin B2; (V) Aflatoxin G2; (VI) Aflatoxin M2; (VII) Tetrahydrodeoxy aflatoxin B1; (VIII) Compound 2; (IX) Compound 8; (X) Compound 11; (XI) Aflatoxin Q1; (XII) Aflatoxin P1; (XIII) Aflatoxin B1-8,9-epoxide. **- Simplified molecular input line entry system (SMILES)<\/p>\n

To study the physiochemical and drug-likeness properties of these thirteen ligands (aflatoxin analogues) Lipinski\u2019s rule of five\/Thumb of five was applied. According to previous studies violation of the Lipinski\u2019s rule of five is when logA is >5, MW >500, number of N, O (hydrogen bond receptor) is >10, number of OH and NH (hydrogen bond donor) is >5 and number of the rotatable bond (rotb) is >15 (21). \u00a0With regard physiochemical properties, all the 13 aflatoxin analogues showed nil violation and complied well with the Lipinski\u2019s rule of five as shown in Table 2.<\/p>\n

Table 2: <\/strong>Molecular physicochemical descriptors analysis of<\/strong> t<\/strong>hirteen aflatoxin analogues using <\/strong>Molinspiration online software tool.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Ligand Names<\/strong><\/td>\nLog Aa<\/sup><\/strong><\/td>\nTPSAb<\/sup><\/strong><\/td>\nNatomsc<\/sup><\/strong><\/td>\nMWd<\/sup><\/strong><\/td>\nnONe<\/sup><\/strong><\/td>\nnOHNHf<\/sup><\/strong><\/td>\nNviolationsg<\/sup><\/strong><\/td>\nNrotbh<\/sup><\/strong><\/td>\nVolumei<\/sup><\/strong><\/td>\n<\/tr>\n
\n
    \n
  1. \u00a0<\/strong><\/li>\n<\/ol>\n<\/td>\n
1.48<\/td>\n74.98<\/td>\n23<\/td>\n321.28<\/td>\n6<\/td>\n0<\/td>\n0<\/td>\n1<\/td>\n253.24<\/td>\n<\/tr>\n
<\/td>\n1.52<\/td>\n84.22<\/td>\n24<\/td>\n328.28<\/td>\n7<\/td>\n0<\/td>\n0<\/td>\n1<\/td>\n262.22<\/td>\n<\/tr>\n
<\/td>\n-0.90<\/td>\n95.21<\/td>\n24<\/td>\n328.28<\/td>\n7<\/td>\n1<\/td>\n0<\/td>\n1<\/td>\n260.93<\/td>\n<\/tr>\n
<\/td>\n1.57<\/td>\n74.98<\/td>\n23<\/td>\n314.29<\/td>\n6<\/td>\n0<\/td>\n0<\/td>\n1<\/td>\n259.42<\/td>\n<\/tr>\n
<\/td>\n1.61<\/td>\n84.22<\/td>\n24<\/td>\n330.29<\/td>\n7<\/td>\n0<\/td>\n0<\/td>\n1<\/td>\n268.41<\/td>\n<\/tr>\n
<\/td>\n1.00<\/td>\n95.21<\/td>\n24<\/td>\n330.29<\/td>\n7<\/td>\n1<\/td>\n0<\/td>\n1<\/td>\n267.12<\/td>\n<\/tr>\n
<\/td>\n2.23<\/td>\n57.91<\/td>\n22<\/td>\n300.31<\/td>\n5<\/td>\n0<\/td>\n0<\/td>\n1<\/td>\n257.24<\/td>\n<\/tr>\n
<\/td>\n2.38<\/td>\n48.68<\/td>\n18<\/td>\n246.26<\/td>\n4<\/td>\n0<\/td>\n0<\/td>\n2<\/td>\n219.24<\/td>\n<\/tr>\n
<\/td>\n1.72<\/td>\n65.75<\/td>\n19<\/td>\n260.25<\/td>\n5<\/td>\n0<\/td>\n0<\/td>\n2<\/td>\n221.42<\/td>\n<\/tr>\n
<\/td>\n1.72<\/td>\n65.75<\/td>\n19<\/td>\n260.25<\/td>\n5<\/td>\n0<\/td>\n0<\/td>\n2<\/td>\n221.42<\/td>\n<\/tr>\n
<\/td>\n0.49<\/td>\n95.21<\/td>\n24<\/td>\n328.28<\/td>\n7<\/td>\n1<\/td>\n0<\/td>\n1<\/td>\n261.28<\/td>\n<\/tr>\n
<\/td>\n1.20<\/td>\n85.98<\/td>\n22<\/td>\n298.25<\/td>\n6<\/td>\n1<\/td>\n0<\/td>\n0<\/td>\n235.71<\/td>\n<\/tr>\n
<\/td>\n1.11<\/td>\n87.51<\/td>\n24<\/td>\n328.28<\/td>\n7<\/td>\n0<\/td>\n0<\/td>\n1<\/td>\n257.62<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Note: <\/strong>a- Octanol-Water partition coefficient, b- Polar surface area, \u00a0c -Number of non-hydrogen atoms, d- Molecular weight, e- Number of hydrogen bond acceptors [ O and N atoms], f -Number of hydrogen bond donors [ OH and NH groups], g- Number of Rule of 5 violations, h- Number of rotatable bonds, i- Molecular volume.<\/p>\n

In the case of drug-likeness if the score\u00a0 > 0 was considered active, -5.0 to -0.0 as moderate active and < -5.0 as inactive (21). All the 13 ligands showed active to moderate active score towards all the six descriptions. Interestingly, none of them showed inactive score as shown in Table 3.<\/p>\n

Table 3: Drug-likeness property analysis of t<\/strong>hirteen aflatoxin analogues using <\/strong>Molinspiration online software tool.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Ligand Names<\/strong><\/td>\nGPCR*<\/sup> ligand<\/strong><\/td>\nIon channel modulator<\/strong><\/td>\nKinase inhibitor<\/strong><\/td>\nNuclear receptor ligand<\/strong><\/td>\nProtease inhibitor<\/strong><\/td>\nEnzyme inhibitor<\/strong><\/td>\n<\/tr>\n
<\/td>\n-0.26<\/td>\n-0.60<\/td>\n-0.43<\/td>\n0.09<\/td>\n-0.36<\/td>\n0.09<\/td>\n<\/tr>\n
<\/td>\n-0.24<\/td>\n-0.51<\/td>\n-0.38<\/td>\n0.01<\/td>\n-0.38<\/td>\n-0.01<\/td>\n<\/tr>\n
<\/td>\n-0.16<\/td>\n-0.52<\/td>\n-0.42<\/td>\n0.21<\/td>\n-0.29<\/td>\n0.18<\/td>\n<\/tr>\n
<\/td>\n-0.22<\/td>\n-0.60<\/td>\n-0.53<\/td>\n0.10<\/td>\n-0.19<\/td>\n0.23<\/td>\n<\/tr>\n
<\/td>\n-0.19<\/td>\n-0.49<\/td>\n-0.47<\/td>\n0.03<\/td>\n-0.02<\/td>\n0.14<\/td>\n<\/tr>\n
<\/td>\n-0.13<\/td>\n-0.48<\/td>\n-0.47<\/td>\n0.26<\/td>\n-0.16<\/td>\n0.29<\/td>\n<\/tr>\n
<\/td>\n-0.37<\/td>\n-0.72<\/td>\n-0.59<\/td>\n-0.05<\/td>\n-0.36<\/td>\n0.11<\/td>\n<\/tr>\n
<\/td>\n-0.78<\/td>\n-0.79<\/td>\n-0.82<\/td>\n-0.26<\/td>\n-0.85<\/td>\n-0.19<\/td>\n<\/tr>\n
<\/td>\n-0.61<\/td>\n-0.71<\/td>\n-0.69<\/td>\n-0.05<\/td>\n-0.65<\/td>\n-0.04<\/td>\n<\/tr>\n
<\/td>\n-0.55<\/td>\n-0.63<\/td>\n-0.70<\/td>\n-0.03<\/td>\n-0.59<\/td>\n0.00<\/td>\n<\/tr>\n
<\/td>\n-0.07<\/td>\n-0.52<\/td>\n-0.34<\/td>\n0.21<\/td>\n-0.22<\/td>\n0.17<\/td>\n<\/tr>\n
<\/td>\n-0.23<\/td>\n-0.53<\/td>\n-0.41<\/td>\n0.23<\/td>\n-0.33<\/td>\n0.22<\/td>\n<\/tr>\n
<\/td>\n-0.23<\/td>\n-0.56<\/td>\n-0.36<\/td>\n0.17<\/td>\n-0.23<\/td>\n0.28<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Note: <\/strong>*GPCR- G Protein coupled receptors<\/p>\n

Similarly, Absorption, Distribution, Metabolism and Excretion (ADME) is simple and essential analysis tool. Recent days, it is commonly accepted in the early stage of drug development program, because of its unique characteristic nature. Table 4 shows the ADME profile of the thirteen selected aflatoxin analogues; all the ligands are predicted to have high gastrointestinal (GI) absorption effect.<\/p>\n

Table 4: ADME (<\/strong>Absorption, Distribution, Metabolism and Excretion) analysis of thirteen <\/strong>aflatoxin analogues using <\/strong>Swiss ADME online tool.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Ligand Names<\/strong><\/td>\nGI absorption<\/strong><\/td>\nBBB permeability<\/strong><\/td>\nP-gp substrate<\/strong><\/td>\n*CYP1A2 inhibitor<\/strong><\/td>\n*CYP2C19 inhibitor<\/strong><\/td>\n*CYP2C9 inhibitor<\/strong><\/td>\n*CYP2D6 inhibitor<\/strong><\/td>\n*CYP3A4 inhibitor<\/strong><\/td>\n# <\/sup><\/strong>Log Kp<\/sub><\/strong><\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nYes<\/td>\nNo<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\nYes<\/td>\nYes<\/td>\n-7.05<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\n-7.05<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\n-7.92<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nYes<\/td>\nNo<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\nYes<\/td>\nYes<\/td>\n-7.27<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\n-7.41<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nYes<\/td>\nYes<\/td>\n-8.14<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nYes<\/td>\nYes<\/td>\nYes<\/td>\nYes<\/td>\nNo<\/td>\nYes<\/td>\nYes<\/td>\n-6.56<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nYes<\/td>\nNo<\/td>\nYes<\/td>\nYes<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\n-6.20<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nYes<\/td>\nNo<\/td>\nYes<\/td>\nYes<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\n-6.95<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nYes<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\n-6.92<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\n-7.94<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nYes<\/td>\nNo<\/td>\n-7.20<\/td>\n<\/tr>\n
<\/td>\nHigh<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nNo<\/td>\nYes<\/td>\nYes<\/td>\n-7.71<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Note<\/strong>: *CYP-Cytochrome P450, #Log Kp -Skin Permeation (cm\/s).<\/p>\n

The docking study and binding site analysis with GSK-3\u03b2, showed that ligand of Aflatoxin G2 exhibited the highest atom contact energy (ACE) of -224.82 kcal\/mol, on other hand Aflatoxin P1 showed the minimum ACE (-160.33 kcal\/mol). \u00a0The binding energy calculation showed the following order: Aflatoxin G2 <\/sub>\u02c2Aflatoxin M1<\/sub>\u02c2Aflatoxin B2<\/sub>\u02c2 AFB1-8,9-epoxy\u02c2Tetrahydreoxy Aflatoxin B1<\/sub> \u02c2 Aflatoxin G1<\/sub>\u02c2 Compound 2= AFQ1\u02c2 Compound 8\u02c2Aflatoxin B1=<\/sub>Aflatoxin M2 \u02c2 Compound 11 \u02c2 AFP1. Further, five ligands (Aflatoxin G1, G2, M2, Tetrahydreoxy Aflatoxin B1 <\/sub>and AFQ1) have shown to interact with Gln185 amino acid residue of GSK-3\u03b2. Interesting another five ligands (Aflatoxin B1, M1 and Compound 2, 8, 11) does not show interaction with amino acid residue of GSK-3\u03b2 (Table 5). Present result infers that the interaction is better for the bio transformed analogues of Aflatoxin (Aflatoxin Q1, Aflatoxin P1, Aflatoxin M2, Tetrahydrodeoxy aflatoxin B1 and AFB1-8, 9-epoxide), rather than the naturally occurring like AFB1, AFGB2 and AFG2.\u00a0 Thus, the present finding was in good agreement with earlier reports (17,27).<\/p>\n

Table 5: The interaction energy analysis of <\/strong>thirteen aflatoxin analogues with Glycogen <\/strong>synthase kinase (GSK) using Patch Dock.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Ligand Names<\/strong><\/td>\nACE* (kcal\/mol)<\/strong><\/td>\nInteraction<\/strong><\/td>\nBonding distance <\/strong>(A\u030a)<\/strong><\/td>\n<\/tr>\n
<\/td>\n-168.64<\/td>\nNo<\/td>\nNil<\/td>\n<\/tr>\n
<\/td>\n-197.50<\/td>\nGln185<\/td>\n1.91<\/td>\n<\/tr>\n
<\/td>\n-216.37<\/td>\nNo<\/td>\nNil<\/td>\n<\/tr>\n
<\/td>\n-210.99<\/td>\nVal 135<\/td>\n3.52<\/td>\n<\/tr>\n
<\/td>\n-224.82<\/td>\nGln 185<\/td>\n2.22<\/td>\n<\/tr>\n
<\/td>\n-168.64<\/td>\nGln 185<\/td>\n3.54<\/td>\n<\/tr>\n
<\/td>\n-197.56<\/td>\nGln 185<\/td>\n2.32<\/td>\n<\/tr>\n
<\/td>\n-195.41<\/td>\nNo<\/td>\nNil<\/td>\n<\/tr>\n
<\/td>\n-183.87<\/td>\nNo<\/td>\nNil<\/td>\n<\/tr>\n
<\/td>\n-163.27<\/td>\nNo<\/td>\nNil<\/td>\n<\/tr>\n
<\/td>\n-195.41<\/td>\nGlu 137<\/td>\n2.61<\/td>\n<\/tr>\n
Gln185<\/td>\n3.16<\/td>\n<\/tr>\n
<\/td>\n-160.33<\/td>\nAsp 200<\/td>\n2.60<\/td>\n<\/tr>\n
<\/td>\n-202.42<\/td>\nVal 135<\/td>\n2.88<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Note: *- Atomic contact energy.<\/strong><\/p>\n

Conclusion<\/strong><\/p>\n

In the present study, all the 13 tested ligands have shown to dock with the target protein Glycogen synthase kinase 3-beta (GSK-3\u03b2). Thus, the present study showed the potential of GSK-3\u03b2 as aflatoxin binder, especially for the bio transformed analogues of Aflatoxin (Aflatoxin Q1, Aflatoxin P1, Aflatoxin M2, Tetrahydrodeoxy aflatoxin B1 and AFB1-8, 9-epoxide).<\/p>\n

Acknowledgment<\/strong><\/p>\n

The authors acknowledges Vel Tech Rangarajan Dr. Sagunthala R & D Institute of Science and Technology for all the support provided during the study and we would like thank Mr. Vijayakumar veeraragavan, Research Scholar, Organic Chemistry Laboratory, Vel Tech Rangarajan Dr.Sagunthala R & D Institute of Science and Technology \u00a0for his help in drawing the chemical structures<\/p>\n

Conflict of interest statement<\/strong><\/p>\n

None declared.<\/p>\n

References<\/strong><\/p>\n

    \n
  1. Pinotti, L., Ottoboni, M., Giromini, C., Dell\u2019Orto, V., Cheli, F., Mycotoxin contamination in the EU feed supply chain: A focus on Cereal Byproducts. Toxins <\/em>8: 45 (2016).<\/li>\n
  2. Vardon, P.J., McLaughlin, C., Nardinelli, C., 2003. Mycotoxins: Risks in plant, animal and human systems. Task Force Report, Council for Agricultural Science and Technology,Ames, Lowa, USA.<\/li>\n
  3. Gratz, S., 2007. Aflatoxin binding by probiotics: Experimental studies on intestinal aflatoxin transport, metabolism and toxicity. Doctoral dissertation, Kuopio University Publications, Kuopio, Finland.<\/li>\n
  4. Kilic, S., Cam, I.B., Tongur, T., Kilic, M., Health risk assessment of exposure to heavy metals and aflatoxins via dietary Intake of dried red pepper from market places in Antalya, Southern Turkey. Journal of Food Science<\/em> 83: 2675-2681 (2018).<\/li>\n
  5. Balina, A., Kebede, A., Tamiru, Y., Review on Aflatoxin and its Impacts on Livestock.\u00a0Journal of Dairy and Veterinary Sciences<\/em> 6: 555685 (2018).<\/li>\n
  6. Eaton, D.L, Gallagher, E.P., Mechanisms of aflatoxin carcinogenesis. Annual Review of\u00a0<\/em>Pharmacology and Toxicology<\/em> 34: 135\u2013172 (1994).<\/li>\n
  7. Gurban, A.M., Epure, P., Oancea, F., Doni, M., Achievements and prospects in electrochemical-based biosensing platforms for aflatoxin M1 detection in milk and dairy products. Sensors<\/em> 17: 1\u201321 (2017).<\/li>\n
  8. Lindahl, J., Kagera, I., Grace, D., Aflatoxin M1 levels in different marketed milk products in Nairobi, Kenya. Mycotoxin Research<\/em> 34: 289-295 (2018).<\/li>\n
  9. Gross-Steinmeyer, K., Eaton, D.L., Dietary modulation of the biotransformation and genotoxicity of aflatoxin B1. Toxicology <\/em>299: 69\u201379 (2012).<\/li>\n
  10. Gizachew, D., Szonyi, B., Tegegne, A., Hanson, J., Grace, D., Aflatoxin contamination of milk and dairy feeds in the Greater Addis Ababa milk shed, Ethiopia. Food Control <\/em>59:773\u2013779 (2016).<\/li>\n
  11. Shigute, T., Washe, A.P., Reduction of aflatoxin M1 Levels during Ethiopian traditional fermented milk (Ergo) production. Journal of Food Quality<\/em> 2018: 4570223 (2018).<\/li>\n
  12. Mohammadi, H., 2011. A Review of aflatoxin M1, milk and milk products. Aflatoxins \u2013 Biochemistry and Molecular Biology, Ramon Gerardo Guevara-Gonzalez, IntechOpen Limited, London, United Kingdom.<\/li>\n
  13. Luo, J., The role of GSK3beta in the development of the central nervous system. Front\u00a0<\/em>Biology<\/em> 7: 212\u2013220 (2012).<\/li>\n
  14. Malagon, S.G.G., Mu\u00f1oz, A.M.L., Doro, D., Bolger, T.G., Poon, E., Tucker, E.R., Al-Lami, H.A., Krause, M., Phiel, C.J., Chesier, L., Liu, K.J., Glycogen synthase kinase 3 controls migration of the neural crest lineage in mouse and Xenopus<\/em>. Nature Communications<\/em> 9:1\u201315 (2018).<\/li>\n
  15. Bustanji, Y., Taha, M.O., Almasri, I.M., Al-Ghussein, M.A., Mohammad, M.K., Alkhatib, H.S., Inhibition of glycogen synthase kinase by curcumin\u202f: Investigation by simulated molecular docking and subsequent in vitro<\/em> \/ in vivo<\/em> evaluation. Journal of Enzyme\u00a0<\/em>Inhibition and Medicinal Chemistry<\/em> 24: 771\u2013778 (2009).<\/li>\n
  16. Varadharaj, V., Kandakati, N., Glycogen synthase kinase-3 beta protein inhibition by selected phytocompounds in silico<\/em>. Asian Journal of Pharmaceutical and Clinical Research\u00a0<\/em>10: 87\u201390 (2017).<\/li>\n
  17. Wang, Y., Liu, J., Zhang, L., He, X., Zhang, J.Z.H., Computational search for aflatoxin binding proteins. Chemical Physics Letters<\/em> 685: 1\u20138 (2017).<\/li>\n
  18. Wogan, G.N., Edwards, G.S., Newberne, P.M., Structure-activity relationships in toxicity and carcinogenicity of aflatoxins and analogs. Cancer Research<\/em> 31: 1936\u20131942 (1971).<\/li>\n
  19. Vijayakumar, V., Radhakrishnan, N., Rameshkumar, C., Molecular docking analysis of<\/li>\n
  20. imidazole derivatives and Polybenzimidazole analogs as inhibitors of Superoxide Dismutase (SOD) and Xanthine Oxidase (XO). IEEE International Conference on Smart\u00a0<\/em>Technologies and Management for Computing, Communication, Controls, Energy and\u00a0<\/em>Materials<\/em> proceedings, <\/em>513 (2017).<\/li>\n
  21. Narayanaswamy, R., Molecular docking analysis of Alginate oligosaccharides ( Alg2-Alg6 ) as bacterial collagenase inhibitor. Journal of Applied Cosmetology<\/em> 35: 15\u201323 (2017).<\/li>\n
  22. Veeraragavan, V., Radhakrishnan, N., Chidambaram, R., Biodegradability nature of Polybenzimidazole analogs by modulating two histidine degradation enzymes (Urocanase and Formiminoglutamase): in silico<\/em> Approach. Asian Journal of Chemistry<\/em> 30: 2205\u20132209 (2018).<\/li>\n
  23. Wang, J., Urban, L., The impact of early ADME profiling on drug discovery and development strategy. Drug Discovery World<\/em> 5: 73\u201396 (2004).<\/li>\n
  24. Van Kessel, T.F.M., Hiang-chek, N., Aflatoxin binders \u2013 how to get the best value for money. International Poultry Production<\/em> 12: 33\u201335 (2018).<\/li>\n
  25. Nazarizadeh, H., Pourreza, J., Evaluation of three mycotoxin binders to prevent the adverse effects of aflatoxin B 1 in growing broilers. Journal of Applied Animal Research\u00a0<\/em>47: 135\u2013139 (2019).<\/li>\n
  26. Tapia-salazar, M., Garc\u00eda-p\u00e9rez, O.D., Nieto-l\u00f3pez, M.G., Villarreal-cavazos, D.A., Cruz- su\u00e1rez, L.E., Ricque-marie, D., Evaluating the efficacy of commercially available aflatoxin binders for decreasing the effects of aflatoxicosis on Pacific white shrimp Litopenaeus\u00a0<\/em>vannamei<\/em>. Hidrobiol\u00f3gica<\/em> 27: 411\u2013418 (2017).Diaz, D.E, Hagler, W.M. Jr., Blackwelder, J.T., Eve, J.A., Brinton, A., Anderson, K.L., Jones, F.T., Whitlow, L.W., Aflatoxin Binders II\u202f: Reduction of aflatoxin M1 in milk by sequestering agents of cows consuming aflatoxin in feed. Mycopathologia<\/em> 157: 233\u2013241(2004).<\/li>\n
  27. Picconi, M.A., Pico, G.A., Gatti, C.A., Fluorometric studies on the binding of aflatoxin B1<\/li>\n
  28. to bovine serum albumin. Health and Environmental Research Online<\/em> 44: 141\u2013148 (1984).<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Introduction Mycotoxins are natural fungal secondary metabolites with low-molecular-weight (i.e., […]<\/p>\n","protected":false},"author":12,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[71],"tags":[],"class_list":["post-28714","post","type-post","status-publish","format-standard","hentry","category-vol12no3"],"_links":{"self":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/28714","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/users\/12"}],"replies":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/comments?post=28714"}],"version-history":[{"count":5,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/28714\/revisions"}],"predecessor-version":[{"id":31961,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/28714\/revisions\/31961"}],"wp:attachment":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/media?parent=28714"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/categories?post=28714"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/tags?post=28714"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}