In-silico Studies of Epoxy-Thioxanthone Derivatives as Potential Tyrosine Kinase Inhibitor Using Molecular Docking, Molecular Dynamics Simulations, MM-PBSA and ADMET
DOI:
https://doi.org/10.1590/Keywords:
Molecular Docking, Molecular Dynamic, ADMET properties, Epoxy thioxanthone, PDGFR, EGFRAbstract
Protein tyrosine kinases play a role in the cell signaling pathways involving cell growth, differentiation, apoptosis, and metabolism of cancer cells. Because of that, the molecular docking, molecular dynamics, MM-PBSA, and prediction ADMET properties were conducted to evaluate the inhibition activity of epoxy-thioxanthones against platelet-derived growth factors receptor (PDGFR) and epidermal growth factor receptor (EGFR) proteins. A series of ten thioxanthone compounds bearing hydroxy, epoxy, chloro, and bromo substituents have been designed and evaluated. The docking results showed that the epoxy-thioxanthones ( A-J ) have binding energy from -7.12 to -9.81 and -7.24 to -8.06 kcal/mol against those proteins, respectively. Compared with the native ligands, all epoxy-thioxanthones gave stronger binding energy (-7.24 to -8.06 kcal/mol) with the active site of EGFR than the erlotinib (-7.05 kcal/mol), which is remarkable. This result is also in line with the molecular dynamics results. The calculation of binding energy MM-PBSA that compounds D , E , I , and J had comparable EGFR protein stability to erlotinib. The binding energy of those compounds (-19.29 to -29.35 kcal/mol) had lower than erlotinib (-8.25 kcal/mol). Furthermore, in physicochemical properties prediction, those compounds fulfill Lipinski’s rule parameters and the minimum standard parameters in ADMET properties.
Downloads
References
Abouantoun TJ, MacDonald TJ. Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor. Mol Cancer Ther. 2009;8(5):1137–1147.
Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7(4):2–8.
Biovia DS. Discovery Studio Visualizer. San Diego: 2019.
Chen CL, Chen TC, Lee CC, Shih LC, Lin CY, Hsieh YY, et al. Synthesis and evaluation of new 3-substituted-4-chloro-thioxanthone derivatives as potent anti-breast cancer agents. Arab J Chem. 2019;12(8):3503–3516.
Claudiani S, Apperley JF. The argument for using imatinib in CML. Hematology Am Soc Hematol Educ Program. 2018;2018(1):161–167.
Cosconati S, Forli S, Perryman AL, Harris R, Goodsell DS, Olson AJ. Virtual screening with AutoDock: theory and practice. Expert Opin Drug Discov. 2010;5(6):597–607.
Coban O, Degim A. Development and validation of highly selective method for the determination of imatinib mesylate and dexketoprofen trometamol combination in three different media. Braz J Pharm Sci. 2020;56:e18583.
da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49–69.
Dolatkhah Z, Javanshir S, Sadr AS, Hosseini J, Sardari S. Synthesis, molecular docking, molecular dynamics studies, and biological evaluation of 4H-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives as potential antileukemic agents. J Chem Int Model. 2017;57(6):1246–1257.
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian-09 Revision D.01. Wallingford CT: Gaussian Inc; 2013.
Hamza MS, Shouman SA, Abdelfattah R, Moussa HS, Omran MM. Determination of the Cut-off Value for Imatinib Plasma Levels Linked to Occurrence of Bone Pain in CML Patients. Drug Des Devel Ther. 2022;16:1595–1604.
Heh CH, Othman R, Buckle MJC, Sharifuddin Y, Yusof R, Rahman NA. Rational discovery of dengue type 2 non-competitive inhibitors. Chem Biol Drug Des. 2013;82(1):1–11.
Hermawan F, Jumina J, Pranowo HD. Design of thioxanthone derivatives as potential tyrosine kinase inhibitor: A molecular docking study. Rasayan J Chem. 2020;13(4):2626–2632.
Hermawan F. Jumina, Pranowo HD, Sholikhah EN, Iresha MR. Molecular docking approach for design and synthesis of thioxanthone derivatives as anticancer agents. ChemistrySelect. 2022;7:e202203076.
Hess B, Kutzner C, van der Spoel D, Lindahl E. GROMACS 4: Algorithms for highly efficient,load-balanced, and scalable molecular simulation. J Chem Theory Comput. 2008;4(3):435–447.
Hirano T, Yasuda H, Tani T, Hamamto J, Oashi A, Ishioka K, et al. In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget. 2015;6(36):38798–38803.
Hospital A, Goni JR, Orozco M, Gelpi JL. Molecular dynamics simulations: advances and applications. Adv Appl Bioinform Chem. 2015;8:37–47.
Huang J, MacKerell Jr AD. CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput Chem. 2013;34(25):2135–2145.
Huey R, Morris GM, Olson AJ, Goodsell DS. A semiempirical free energy force field with charge‐based desolvation. J Comput Chem. 2007;28(6):1145–1152.
Hünenberger PH. Thermostat algorithms for molecular dynamics simulations. Adv. Polymer. Sci. 2005;173:105–149.
Ismail RSM, Ismail NSM, Abuserii S, El-Ella DAA. Recent advances in 4-aminoquinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents. Future J Pharm Sci. 2016;2:09–19.
Kanaan R, Strange C. Use of multitarget tyrosine kinase inhibitors to attenuate platelet-derived growth factor signalling in lung disease. Eur Respir Rev. 2017;26(146):170061.
Karabacak M, Altıntop MD, Çiftçi HI, Koga R, Otsuka M, Fujita M, et al. Synthesis and evaluation of new pyrazoline derivatives as potential anticancer agents. Molecules. 2015;20(10):19066–19084.
Kumari R, Kumar R, Lynn A. g_mmpbsa—a GROMACS tool for high-throughput MM-PBSA calculations. J. Chem. Inf. Model. 2014;54(7):1951–1962.
Kupchan, SM, Streelman DR, Sneden AT. Psorospermin, a new antileukemic xanthone from Psorospermum febrifugum. J. Nat. Prod. 1980;43:296–301.
Liang W, Wu X, Fang W, Zao Y, Yang Y, Hu Z, et al. Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. PLoS One. 2014;9(2):e85245.
Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug discovery today. Technologies. 2004;1(4):337–341.
Martonák R, Laio A, Parrinello M. Predicting crystal structures: the parrinello-rahman method revisited. Phys. Rev. Lett. 2003;90(7):075503.
Matei D, Chang DD, Jeng MH. Imatinib mesylate (Gleevec) inhibits ovarian cancer cell growth through a mechanism dependent on platelet-derived growth factor receptor alpha and Akt inactivation. Clin Cancer Res. 2004;10(2):681–690.
McConkey BJ, Sobolev V, Edelman M. The performance of current methods in ligand-protein docking. Curr Sci. 2002;83(7):845–855.
Morris GM, Huey R, Lindstrom W, Sanner MF,Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785–2791.
Mukesh B, Rakesh K. Molecular docking: A review. Int J Res Ayurveda Pharm. 2011;2:1746–1751.
Na Y. Recent cancer drug development with xanthone structures. J Pharm Pharmacol. 2009;61(6):707–712.
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605–1612.
Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem. 2015;58(9):4066–4072.
Pronk S, Páll S, Schulz R, Larsson P, Bjelmar P, Apostolov R, et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013;29(7):845–854.
Shah A, Sanghvi K, Sureja D, Seth AK. In-silico drug design and molecular docking studies of some natural products as tyrosine kinase inhibitors. Int J Pharm Res. 2018;10(2):256–260.
Singh P, Bast F. In-silico molecular docking study of natural compounds on wild and mutated epidermal growth factor receptor. Med Chem Res. 2014;23(12):5074–5085.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249.
Verlet L. Computer “experiments” on classical fluids. i. thermodynamical properties of lennard-jones molecules. Phys Rev. 1967;159:98–103.
Vijesh AM, Isloor AM, Telker S, Arulmoli T, Fun HK. Molecular docking studies of some new imidazole derivatives for antimicrobial properties. Arab J Chem. 2013;6(2):197–204.
Wahyuningsih TD, Suma AAT, Astuti E. Synthesis, anticancer activity, and docking study of N-acetyl pyrazolines from veratraldehyde. J Appl Pharm Sci. 2019;9(3):14–20.
Woo S, Jung J, Lee C, Kwon Y, Na Y. Synthesis of new xanthone analogues and their biological activity test cytotoxicity, topoisimerase II inhibition and DNA cross-linking study. Bioorg Med Chem Lett. 2007;17(5):1163–1166.
Woo S, Kang D, Kim J, Lee E, Jahng Y, Kwon Y, Na Y. Synthesis, cytotoxicity and topoisomerase ii inhibition study of new thioxanthone analogues. Bull Korean Chem Soc. 2008;29(2):471-474.
Woo S, Kang D, Nam JM, Lee CS, Ha E, Lee E, Kwon Y, Na Y. Synthesis and pharmacological evaluation of new methyloxiranylmethoxyxanthone analogues. Eur J Med Chem. 2010;45(9):4221–4228.
Yuanita E, Pranowo HD, Mustofa M, Swasono RT, Syahri J, Jumina J. Synthesis characterization and molecular docking of chloro-substituted hydroxyxanthone derivatives. Chem J Mold. 2019;14(1):68–76.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on-line journal has open and free access.
