Document Type : Original Research Article

Authors

1 Research and Development Department, Shari Pharmaceutical Company, Tehran, Iran

2 Department of Science, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran

3 Science and Research Branch, Islamic Azad University, Tehran, Iran

4 LorestanPhysics Department, Faculty of Science, Lorestan University, Khorramabad, Iran

10.33945/SAMI/AJCB.2020.1.5

Abstract

The main purpose of present study is evaluation of structural and medicinal properties for Withaferin A (WIT) using density functional theory (DFT) method. All studies are done via computational chemistry methods using Gaussian 03 and Molegro Virtual Docker (MVD) software packages and SwissADME web-based tool. Molecular structure of WIT was optimized at the B3LYP/6-311++G(d,p) theoretical level of DFT. The reactivity and stability properties of the optimized molecule were explored via global reactivity indices. Calculating the reactivity indices using energies of frontier molecular orbitals (FMOs) showed that WIT is stable against the oxidizing agents in the cell and has low reactivity against the biomolecules. On the other hand, the docking analysis data indicated the steric interactions play important role in WIT binding to beta-Tubulin via the residues Tyr224, Cys12, Gln11, Asn101, Gly143, Gln15, Gly144, Asn206, Gly142, and Asp179.

Graphical Abstract

Withaferin A (WIT) Interaction with beta–Tubulin to Promote Tubulin Degradation: In Silico Study

Keywords

  1. Balaguer FD, Mühlethaler T, Estévez-Gallego J, Calvo E, Giménez-Abián JF, Risinger AL, Sorensen EJ, Vanderwal CD, Altmann KH, Mooberry SL, Steinmetz MO. Crystal structure of the cyclostreptin-tubulin adduct: implications for tubulin activation by taxane-site ligands. Int. J. Mol. Sci. 2019;20:1392.
  2. Bargagna-Mohan P, Hamza A, Kim YE, Ho YK, Mor-Vaknin N, Wendschlag N, Liu J, Evans RM, Markovitz DM, Zhan CG, Kim KB. The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin. Chem. Biol. 2007;14:623-634.
  3. Buey RM, Calvo E, Barasoain I, Pineda O, Edler MC, Matesanz R, Cerezo G, Vanderwal CD, Day BW, Sorensen EJ, López JA. Cyclostreptin binds covalently to microtubule pores and lumenal taxoid binding sites. Nature Chem. Biol. 2007;3:117-125.
  4. Drahl C, Cravatt BF, Sorensen EJ. Protein‐reactive natural products. Angew. Chem. 2005;44:5788-5809.
  5. Dumontet C, Jordan MA. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nature Rev. Drug Discover. 2010;9:790-803.
  6. Hamel E. An overview of compounds that interact with tubulin and their effects on microtubule assembly. In The Role of Microtubules in Cell Biology, Neurobiology, and Oncology. Humana Press; 2008. pp. 1-19.
  7. Falsey RR, Marron MT, Gunaherath GK, Shirahatti N, Mahadevan D, Gunatilaka AL, Whitesell L. Actin microfilament aggregation induced by withaferin A is mediated annexin II. Nature Chem. Biol. 2006;2:33-38.
  8. Fortin S, Lacroix J, Côté MF, Moreau E, Petitclerc É, René C. Quick and simple detection technique to assess the binding of antimicrotubule agents to the colchicine-binding site. Biol. Proc. Online 2010;12:113-117.
  9. Gambhir L, Checker R, Sharma D, Thoh M, Patil A, Degani M, Gota V, Sandur SK. Thiol dependent NF-κB suppression and inhibition of T-cell mediated adaptive immune responses by a naturally occurring steroidal lactone Withaferin A. Toxicol. Appl. Pharmacol. 2015;289:297-312.
  10. Gigant B, Wang C, Ravelli RB, Roussi F, Steinmetz MO, Curmi PA, Sobel A, Knossow M. Structural basis for the regulation of tubulin by vinblastine. Nature 2005;435:519-522.
  11. Gu M, Yu Y, Gunaherath GK, Gunatilaka AL, Li D, Sun D. Structure-activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells. Invest. New Drugs 2014;32:68-74.
  12. Heyninck K, Lahtela-Kakkonen M, Van der Veken P, Haegeman G, Berghe WV. Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ. Biochemical pharmacology. 2014;91:501-509.
  13. Antony ML, Lee J, Hahm ER, Kim SH, Marcus AI, Kumari V, Ji X, Yang Z, Vowell CL, Wipf P, Uechi GT. Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of β-tubulin. J. Biol. Chem. 2014;289:1852-1865.
  14. Yang J, Yan W, Li Y, Niu L, Ye H, Chen L. The natural compound Withaferin A covalently binds to Cys239 of β-tubulin to promote tubulin degradation. Mol. Pharmacol. 2019;96:711-719.
  15. Nabati M, Bodaghi-Namileh V. Molecular modeling of 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate and its molecular docking study with phosphodiesterase-5 (PDE5). Adv. J. Chem. A 2020;3:58-69.
  16. Nabati M, Lohrasbi E, Sabahnoo H, Bodaghi-Namileh V, Mazidi M, Mohammadnejad-Mehrabani H, Tavakkoli A, Gervand A. In silico study of metoclopramide as a small molecule of dopamine D2 receptor. Chem. Method. 2020;4:19-33.
  17. Nabati M. Exploring molecular docking and electronic studies of [11C] LY2795050 as a novel antagonist tracer for positron emission tomography (PET) scan of the kappa (κ) and mu (µ) opioid receptors (KOR and MOR). J. Med. Chem. Sci. 2020;3:22-34.
  18. Nabati M, Bodaghi-Namileh V. In silico study of the active components (17α-ethinyl estradiol and segesterone acetate) of annovera as a novel vaginal contraceptive system by docking of their binding to estrogen and progesterone receptors. Iran. Chem. Commun. 2020;8:73-85.
  19. Nazemi H, Mirzaei M, Jafari E. Antidepressant Activity of Curcumin by Monoamine Oxidase–A Inhibition. Adv. J. Chem. B 2019;1:3-9.
  20. Ozkendir O, Mirzaei M. Alkali metal chelation by 3–hydroxy–4–pyridinone. Adv. J. Chem. B 2019;1:10-16.
  21. Esfahani, A., Mirzaei, M. Flavonoid derivatives for monoamine oxidase–A inhibition. Adv. J. Chem. B 2019;1:17-22.
  22. Alidoosti Z, Mirzaei M. Comparative examination of moclobemide, tranylcypromine, phenelzine and isocarboxazid for monoamine oxidase–A inhibition. Adv. J. Chem. B 2019;1:23-28.
  23. Ariaei S. Adsorptions of diatomic gaseous molecules (H2, N2 and CO) on the surface of Li+@C16B8P8 fullerene-like nanostructure: computational studies. Adv. J. Chem. B 2019;1:29-36.
  24. Soleimani M, Mirzaei M, Mofid MR, Khodarahmi G, Rahimpour SF. Lactoperoxidase inhibition by tautomeric propylthiouracils. Asian J. Green Chem. 2020;4:1-10.
  25. Samadi Z, Mirzaei M, Hadipour NL, Khorami SA. Density functional calculations of oxygen, nitrogen and hydrogen electric field gradient and chemical shielding tensors to study hydrogen bonding properties of peptide group (O=C–NH) in crystalline acetamide. J. Mol. Graph. Model. 2008;26:977-981.
  26. Davarpanah M, Abbasi H, Nabati M, Sabahnoo H, Bodaghi-Namileh V, Mazidi M, Movahhed-Tazehkand H, Mohammadnejad-Mehrabani H. Kit formulation of active pharmaceutical ingredient d, l-HMPAO as a brain perfusion diagnostic system. Prog. Chem. Biochem. Res. 2019;2:185-191.
  27. Nabati M, Bodaghi-Namileh V, Sarshar S. Molecular modeling of the antagonist compound esketamine and its molecular docking study with non-competitive N-methyl-D-aspartate (NMDA) receptors NR1, NR2A, NR2B and NR2D. Prog. Chem. Biochem. Res. 2019;2:108-119.
  28. Nabati M, Bodaghi-Namileh V. Non-competitive N-methyl-D-aspartate (NMDA) receptor (NR2B) structure in complex with antidepressant arketamine. Iran. J. Org. Chem. 2019;11:2591-2598.
  29. Nabati M, Bodaghi-Namileh V. Design of novel drugs (P3TZ, H2P3TZ, M2P3TZ, H4P3TZ and M4P3TZ) based on zonisamide for autism treatment by binding to potassium voltage-gated channel subfamily D member 2 (Kv4. 2). Int. J. New Chem. 2019;6:254-276.
  30. Nabati M, Sabahnoo H. Spectroscopic (FT-IR and UV-Vis), electronic and docking studies on the red clover isoflavone irilone as a progesterone receptor (PR) effect supporter in endometrial and ovarian cancer cell lines. J. Med. Chem. Sci. 2019;2:118-125.
  31. Nabati M. Modeling and interactions analysis of the novel antagonist agent flibanserin with 5-hydroxytryptamine 2A (5-HT2A) serotonin receptor as a HSDD treatment in premenopausal women. Iran. Chem. Commun. 2019;7:324-334.
  32. Nabati M, Sabahnoo H, Lohrasbi E, Mazidi M. Structural Properties Study and Spectroscopic (FT-IR and UV-Vis) Profiling of the Novel Antagonist LY2157299 as a Transforming Growth Factor-β (TGF-β) Receptor I Kinase Inhibitor by Quantum-mechanical (QM) and molecular docking techniques. Chem. Method. 2019;3:377-391.
  33. Nabati M. Insight into the structural and spectral (IR and UV-Vis) properties of the salts of alkali (Li, Na and K) and alkaline earth (Be, Mg and Ca) metals with pertechnetate oxoanion (99mTcO4-) as the convenient water-soluble sources of the radioactive element technetium. Chem. Method. 2019;3:258-270.
  34. Nabati M, Bodaghi-Namileh V. Physicochemical properties analysis and dopamine D2 receptor (D2R) docking of zotepine as an atypical antipsychotic antagonist. J. Phys. Theor. Chem. 2018;15:149-157.
  35. Nabati M, Bodaghi-Namileh V, Mazidi M. Evaluation of [18F] FPTT molecular structure and its binding to progesterone receptor (PR) for PET scan of breast cancer. J. Phys. Theor. Chem. 2018;15:159-171.