In silico Molecular Docking, Molecular Dynamic Simulation and ADME Study of New (2-Methyl Benzimidazole-1-yl)-N- Derivatives with Potential Anti-proliferative Activity

Year 2025, , 115 - 128, 05.01.2025

Mariam Saeb , Monther Faisal Mahdi Foad A. Al-saady

https://doi.org/10.33435/tcandtc.1442921

Abstract

ABSTRACT

Although there has been great progress in the development of anticancer medications, numerous obstacles remain, including drug resistance, poor effectiveness, and excessive toxicity, which have all profoundly impacted the daily lives of cancer patients. Because of this, finding highly selective, effective, and non-toxic anticancer drugs is a major challenge in current cancer research.
We present an in silico evaluation of a new series of 2-methylbenzimidazole derivatives to determine the anti-proliferative effect in the epidermal growth factor receptor (EGFR) active sites.
Our six compounds docked with the EGFR crystal structure (protein data bank code: 4HJO) to determine their binding affinity to active sites.
One of these compounds showed a high score (75.5) and two compounds had as binding energy as the gold standard drug erlotinib.
The molecular dynamic simulation study revealed that compound 1 had good alignment with the EGFR receptor
according to Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) data.
After analyzing the ADME study of virtually active compounds, they achieved Lipinski's rules, and other pharmacokinetic properties.
Lastly, these compounds can function as precursors for the development of novel anti-proliferative drug.

Keywords

molecular docking, molecular dynamic, ADME, 2-Methylbenzimidazole, EGFRinhibitors, anti-proliferative

References

• [1] M.J. Meegan, N.M. O’Boyle, Special Issue “Anticancer Drugs”, Pharmaceuticals. 12(3) (2019) 134.
• [2] J. Sun, J. Mu, S. Wang, C. Jia, D. Li, H. Hua H., H. Cao, Design and synthesis of chromone-nitrogen mustard derivatives and evaluation of anti-breast cancer activity, Journal of Enzyme Inhibition and Medicinal Chemistry 37(1) (2022) 437–450.
• [3] V. Soo, B. Kwan, H. Quezada, I. Castillo-Juárez, B. Pérez-Eretza, García-Contreras S., et al. Repurposing of anticancer drugs for the treatment of bacterial infections. Current Topics in Medicinal Chemistry17(10) (2017) 1157–76.
• [4] B. Mansoori, A. Mohammadi, S. Davudian, S. Shirjang, B. Baradaran, The different mechanisms of cancer drug resistance: A brief review. Advanced Pharmaceutical Bulletin 7(3) (2017) 339-348.
• [5] Z. Abbas, S. Rehman, In: Neoplasm, An Overview of Cancer Treatment Modalities, IntechOpen, (2018).
• [6] W. You, M. Henneberg, Cancer incidence increasing globally: The role of relaxed natural selection. Evolutionary Applications 11(2) (2017) 140–152.
• [7] F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics, GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. A Cancer Journal for Clinicians 68(6) (2018) 394–424.
• [8] B.S.P. Sandor, S.P. Eckhardt, Recent progress in the development of anticancer agents. Current Medicinal Chemistry-Anti-Cancer Agents 2(3) (2002) 419–439.
• [9] O.O. Fadeyi O.O., Adamson S.T., Myles E.L., Okoro C.O. Novel fluorinated acridone derivatives. Part 1: Synthesis and evaluation as potential anticancer agents. Bioorganic & Medicinal Chemistry Letters 18 (14) (2008) 4172–4176.
• [10] R.G. McKinnell, R.E. Parchment, A.O. Perantoni, G.B. Pierce, I. Damjanov, The Biological Basis of Cancer, Cambridge, 1998, 14–50.
• [11] H. Tanaka, H. Matsushima, N.A. Mizumoto, Takashima, Classification of chemotherapeutic agents based on their differential in vitro impacts on dendritic cells. Cancer research 69(17) (2009) 6978-6986.
• [12] S.Z. Lutz, J. Hennenlotter, M.O. Scharpf, C. Sailer, L. Fritsche, V. Schmid, K. Kantartzis, Androgen receptor overexpression in prostate cancer in type 2 diabetes. Molecular metabolism. 8 (2018) 158-166.
• [13] C. Pottier, M. Fresnais, M. Gilon, G. Jérusalem, R. Longuespée, N.E. Sounni, Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers. 12(3) (2020) 731.
• [14] H. Kwon, S.H. Son, Y. Byun, Prostate‐specific membrane antigen (PSMA)‐targeted radionuclide probes for imaging and therapy of prostate cancer. Asian Journal of Organic Chemistry 8(9) (2019) 1588-1600.
• [15] S.C. Chafe, P.C. McDonald, S. Saberi, O. Nemirovsky, G. Venkateswaran, S. Burugu, ... & S. Dedhar, Targeting hypoxia-induced carbonic anhydrase IX enhances immune-checkpoint blockade locally and systemically. Cancer immunology research 7(7) (2019) 1064-1078.
• [16] K. Li, W. Dong, Q. Liu, G. Lv, M. Xie, X. Sun, L. Qiu, & J. Lin, A biotin receptor-targeted silicon(IV) phthalocyanine for in vivo tumor imaging and photodynamic therapy. Journal of Photochemistry and Photobiology B: Biology, 190 (2019) 1-7.
• [17] L. Wang, W. Zhou, Y. Zhong, Y. Huo, P Fan, S. Zhan, J. Xiao, X. Jin, S. Gou, T. Yin, H. Wu, & T. Liu, Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-κB signaling pathway. Molecular cancer, 16(1) (2017) 61.
• [18] G. Sherbet, Breast cancer and therapeutic deployment of growth factor receptors. British Journal of Medical Practitioners. 2(2) (2009) 6-10.
• [19] M. Fernandez, F. Javaid, V. Chudasama, Advances in targeting the folate receptor in the treatment/imaging of cancers. Chemical science 9 (2017).
• [20] M.K. Paul, A.K. Mukhopadhyay, Tyrosine kinase–role and significance in cancer. International journal of medical sciences 1(2) (2004) 101.
• [21] K. Gabora, A. Piciu, I.C. Bădulescu, M.I. Larg, I.A. Stoian, & D. Piciu, Current evidence on thyroid related adverse events in patients treated with protein tyrosine kinase inhibitors. Drug Metabolism Reviews 51(4) (2019) 562-569.
• [22] T. Koppal, Neglected kinase targets are now in vogue. Drug Disc Develop, (2003) 75-80.
• [23] F. Ciardiello, F. De Vita, M. Orditura, & G. Tortora, The role of EGFR inhibitors in nonsmall cell lung cancer. Current Opinion in Oncology 16(2) (2004) 130-5.
• [24] V.K. Mehta, Radiotherapy and erlotinib combined: review of the preclinical and clinical evidence. Frontiers in Oncology 2 (2012) 2.
• [25] D. Li, M. Li, H. Li, P. Shi, M. Chen, T. Yang The use of cytotoxic drugs as first-line chemotherapy for EGFR (+) nonsquamous NSCLC: A network meta-analysis. Disease Markers (2023) 1–8
• [26] P.A. Tang, M.S. Tsao, M.J. Moore, A review of erlotinib and its clinical use. Expert Opin Pharmacother 7(2) (2006) 177–93.
• [27] N. Kerru, L. Gummidi, S. Maddila, K.K. Gangu, S.B. Jonnalagadda, A review of recent advances in nitrogen-containing molecules and their biological applications. Molecules 25(8) (2020) 1909.
• [28] N. Kerru, L. Gummidi, S. Maddila, K.K. Gangu, S.B. Jonnalagadda A review on recent advances in nitrogen-containing molecules and their biological applications. Molecules 25(8) (2020) 1909.
• [29] F.H. Abdulredha, M.F. Mahdi, A.K. Khan, In silico evaluation of binding interaction and ADME study of new 1,3-diazetidin-2-one derivatives with high antiproliferative activity. Journal of advanced pharmaceutical technology and research. 14(3) (2023) 176-184.
• [30] L.B. Townsend, Revankar G.R. Benzimidazole nucleosides, nucleotides, and related derivatives. Chemical Reviews Journal 70 (3) (1970) 389-438.
• [31] J. Akhtar, A.A. Khan, Z. Ali, R. Haider, M. Shahar Yar, Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur J Med Chem 125 (2017) 143–189.
• [32] D. Carcanague, Y.K. Shue, M.A. Wuonola, M. Uria-Nickelsen, C. Joubran, J.K. Abedi, J. Jones, & Kühler, T. C, Novel structures derived from 2-[[(2-Pyridyl)methyl]thio]-1H-benzimidazole as anti-Helicobacter pylori agents, part 2. Journal of Medicinal Chemistry 45(19) (2002) 4300–4309.
• [33] N.M. Aghatabay, M. Somer, M. Senel, B. Dulger, F. Gucin, Raman, FT-IR, NMR spectroscopic data and antimicrobial activity of bis[μ2-(benzimidazol-2-yl)-2-ethanethiolato-N,S,S-chloro-palladium(II)] dimer, [(μ2-CH2CH2NHNCC6H4)PdCl]2·C2H5OH complex. European Journal of Medicinal Chemistry 42(8) (2007) 1069–1075.
• [34] S. Demirayak, A.C. Karaburun, I. Kayagil, U. Uçucu, R. Beis, Synthesis and analgesic activities of some 2-(benzazolylacetyl)amino-3-ethoxycarbonylthiophene derivatives. Phosphorus, Sulfur, and Silicon and the Related Elements 180(8) (2005) 1841–1848.
• [35] A. Locatelli, S. Cosconati, M. Micucci, A. Leoni, L. Marinelli, A. Bedini, et al. Ligand-based approach to L-type calcium channel by imidazo[2,1-b]thiazole-1,4-dihydropyridines: From heart activity to brain affinity. Journal of Medicinal Chemistry 56(10) (2013) 3866–3877.
• [36] Yadav G., Ganguly S. Structure-activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review. European Journal of Medicinal Chemistry 97 (2015) 419–443.
• [37] M. Gaba, P. Gaba, D. Uppal, N. Dhingra, M.S. Bahia, O. Silakari, C. Mohan, Benzimidazole derivatives: search for GI-friendly anti-inflammatory analgesic agents. Acta Pharmaceutica Sinica B. 5(4) (2015) 337–342.
• [38] M. Gaba, C. Mohan, Development of drugs based on imidazole and benzimidazole bioactive heterocycles: recent advances and future directions. Medicinal Chemistry Research. 25(2) (2016) 173–210.
• [39] R.C. Boruah, E. B. & Skibo, A Comparison of the Cytotoxic and Physical Properties of Aziridinyl Quinone Derivatives Based on the Pyrrolo[1,2-a]benzimidazole and Pyrrolo[1,2-a]indole Ring Systems. Journal of Medicinal Chemistry, 37(11) (1994), 1625-1631.
• [40] M.H. Pourgholami, L. Woon, R. Almajd, J. Akhter, P. Bowery, & D.L. Morris, In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole. Cancer letters, 165(1), (2001),43–49.
• [41] D.L. Morris, J.L. Jourdan, & M.H. Pourgholami, Pilot study of albendazole in patients with advanced malignancy: Effect on serum tumor markers/high incidence of neutropenia. Oncology, 61(1), (2001), 42–46.
• [42] K. Kamanna, In: Chemistry and Applications of Benzimidazole and Its Derivatives, Synthesis and pharmacological profile of benzimidazoles. IntechOpen, London, UK, (2019) 51–69.
• [43] N. Shrivastava, M.J. Naim, M. J. Alam, F. Nawaz, S. Ahmed, & O. Alam, Benzimidazole Scaffold as Anticancer Agent: Synthetic Approaches and Structure-Activity Relationship. Archiv der Pharmazie, 350(6), (2017).
• [44] Y.T. Lee, Y.J. Tan, & C. Oon, E.,Benzimidazole and its derivatives as cancer therapeutics: The potential role from traditional to precision medicine. Acta pharmaceutica Sinica. B, 13(2), (2023) 478–497.
• [45] K.R. Cousins, ChemDraw Ultra 9.0. CambridgeSoft, 100 CambridgePark Drive, Cambridge, MA 02140. www. cambridgesoft.com. See Web site for pricing options. Journal of the American Chemical Society 127(11), (2005),4115-4116.
• [46] G. Jones, P. Willett, R.C. Glen, A.R. Leach, R. Taylor, Development and validation of a genetic algorithm for flexible docking. Journal of molecular biology,267(3),( 1997),727-48.
• [47] Jones G, Willett P, Glen RC. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. Journal of molecular biology. 245(1),( 1995 ),43-53.
• [48] Huang SY, Zou X. Ensemble docking of multiple protein structures: considering protein structural variations in molecular docking. Proteins: Structure, Function, and Bioinformatics.66(2),( 2007),399-421.
• [49] Siva Kumar, B., Anuragh, S., Kammala, A. K., & Ilango, K., Computer Aided Drug Design Approach to Screen Phytoconstituents of Adhatoda vasica as Potential Inhibitors of SARS-CoV-2 Main Protease Enzyme. Life (Basel, Switzerland), 12(2), (2022), 315.
• [50] Y.M. Khetmalis, S. Chitti, A.U. Wunnava, B.K. Kumar, M.K. Kumar, S. Murugesan, & K.V.G.C. Sekhar, Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-a]pyridine analogues. RSC medicinal chemistry, 13(3), (2022),327–342.
• [51] A. Daina, O. Michielin, & V. Zoete, SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports, 7, 42717, (2017).
• [52] T. Oashi, A.L. Ringer, E.P. Raman, & A.D. Mackerell, Automated selection of compounds with physicochemical properties to maximize bioavailability and druglikeness. Journal of chemical information and modeling, 51(1), (2011),148–158.