In Silico Prediction of EGFR Inhibitors from Thiophene Derivatives

Year 2024, Volume: 7 Issue: 6, 1131 - 1138, 15.11.2024

Pınar Siyah

https://doi.org/10.34248/bsengineering.1537989

Abstract

Cancer is one of the biggest global health problems and is the second leading cause of death worldwide. Cancer also causes great damage to economy. Unfortunately, there is still no effective treatment method against this disease today, and the mortality rates in certain types are still very high. Medical research can now be done faster and safer with the aid of in silico studies. These studies save time for researchers and accelerate new drug discoveries. In our study, thiophene derivatives with important efficacy in cancer treatment were focused on and the affinity of the small molecule structures determined as candidates to the Epidermal Growth Factor Receptor (EGFR), known to be the key receptor in cancer, was examined. First, molecular docking studies were performed, and then long-term molecular dynamics (MD) simulations were carried out. Finally, anti-cancer activity predictions based on Quantitative Structure-Activity Relationship (QSAR) were performed. Co-crystallized ligand Erlotinib, taken from the Protein Data Bank (PDB), was used as a positive control and compared with candidate drugs using the same procedures. In light of the analysis of virtual screening, MD, MM/GBSA, and QSAR predictions, the top three molecules and their MM/GBSA scores were identified as follows: OSI 930 (-65.81 kcal/mol), Neltenexine (-49.53 kcal/mol), and Tenonitrozole (-41.95 kcal/mol). As a result, in this study, candidate molecules that inhibit EGFR and have the highest potential as anti-cancer drugs among thiophene-derived compounds were determined and detailed in silico analyzes were performed. This study holds importance as it may guide future anti-cancer drug discovery studies.

Keywords

EGFR, MD simulation, Molecular docking, Small molecules, Thiophene derivatives

References

• Agarwal G, Hajra A, Chakraborty S, Patel N, Biswas S, Adler MK, Lavie CJ. 2022. Predictors and mortality risk of venous thromboembolism in patients with COVID-19: systematic review and meta-analysis of observational studies. Ther Adv Cardiovasc Dis, 16: 17539447221105012.
• Bas DC, Rogers DM, Jensen JH. 2008. Very fast prediction and rationalization of pKa values for protein–ligand complexes. Proteins, 73(3): 765-783.
• Berdigaliyev N, Aljofan M. 2020. An overview of drug discovery and development. Future Med Chem, 12(10): 939-947.
• Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Sacerdoti FD. 2006. Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proc. 2006 ACM/IEEE Conf. Supercomput, November 11-17, New York, NY, United States, pp: 84.
• Braga PC, Piatti G, Limoli A, Dal Sasso M, Maci S. 1995. Neltenexine: morphological investigation of protection against elastase-induced emphysema in rats. Drugs Exp Clin Res, 21(2): 51-57.
• Cattaneo C. 2001. Neltenexine tablets in smoking and non-smoking patients with COPD. A double-blind, randomised, controlled study versus placebo. Minerva Med, 92(4): 277-284.
• Celik I, Ayhan-Kılcıgil G, Karayel A, Guven B, Onay-Besikci A. 2022. Synthesis, molecular docking, in silico ADME, and EGFR kinase inhibitor activity studies of some new benzimidazole derivatives bearing thiosemicarbazide, triazole, and thiadiazole. J Heterocycl Chem, 59(2): 371-387.
• Chunaifah I, Venilita RE, Tjitda PJP, Astuti E, Wahyuningsih TD. 2024. Thiophene-based N-phenyl pyrazolines: Synthesis, anticancer activity, molecular docking and ADME study. J Appl Pharm Sci, 14(4): 63-71.
• Collaboration GB of DC. 2019. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. JAMA Oncol, 5(12): 1749-1768. doi:10.1001/jamaoncol.2019.2996
• da Silva Santos E, Nogueira KAB, Fernandes LCC, Martins JRP, Reis AVF, Neto JdeBV, Eloy JO. 2021. EGFR targeting for cancer therapy: Pharmacology and immunoconjugates with drugs and nanoparticles. Int J Pharm, 592: 120082.
• Durdagi S. 2020. Virtual drug repurposing study against SARS-CoV-2 TMPRSS2 target. Turk. J. Biol., 44(7): 185-191.
• Ekins S, Bugrim A, Brovold L, Kirillov E, Nikolsky Y, Rakhmatulin E, Melnikov A. 2006. Algorithms for network analysis in systems-ADME/Tox using the MetaCore and MetaDrug platforms. Xenobiotica, 36(10-11): 877-901.
• Eldehna WM, El Hassab MA, Elsayed ZM, Al-Warhi T, Elkady H, Abo-Ashour MF, Abdel-Aziz HA. 2022. Design, synthesis, in vitro biological assessment and molecular modeling insights for novel 3-(naphthalen-1-yl)-4, 5-dihydropyrazoles as anticancer agents with potential EGFR inhibitory activity. Sci Rep, 12(1): 12821.
• Evans DJ, Holian BL. 1985. The nose–hoover thermostat. J Chem Phys, 83(8): 4069-4074.
• Falchook GS, Kurzrock R. 2015. VEGF and dual-EGFR inhibition in colorectal cancer. Cell Cycle, 14(8): 1129-1130.
• Gagic Z, Ruzic D, Djokovic N, Djikic T, Nikolic K. 2020. In silico methods for design of kinase inhibitors as anticancer drugs. Front Chem, 7: 873.
• Garton AJ, Crew APA, Franklin M, Cooke AR, Wynne GM, Castaldo L, Brown EN. 2006. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res, 66(2): 1015-1024.
• Gramec D, Peterlin Mašič L, Sollner Dolenc M. 2014. Bioactivation potential of thiophene-containing drugs. Chem Res Toxicol, 27(8): 1344-1358.
• Guo M, Yu X, Zhu YZ, Yu Y. 2023. From bench to bedside: What do we know about imidazothiazole derivatives so far? Molecules, 28(13): 5052.
• Harmanen M, Klaavuniemi T, Sorigue M, Khan M, Prusila R, Kari E, Jukkola A. 2023. Real-world Data: MCL2 protocol demonstrates excellent treatment results among patients with mantle cell lymphoma not fulfilling the original trial inclusion criteria. HemaSphere, 7(10): e954.
• Jacobson MP, Pincus DL, Rapp CS, Day TJF, Honig B, Shaw DE, Friesner RA. 2004. A hierarchical approach to all-atom protein loop prediction. Proteins, 55(2): 351-367.
• Jamal S, Goyal S, Shanker A, Grover A. 2015. Checking the STEP-associated trafficking and internalization of glutamate receptors for reduced cognitive deficits: a machine learning approach-based cheminformatics study and its application for drug repurposing. PLoS One, 10(6): e0129370.
• Jones W, Tait D, Livasy C, Ganapathi M, Ganapathi R. 2022. PLK3 amplification and tumor immune microenvironment of metastatic tumors are linked to adjuvant treatment outcomes in uterine serous cancer. NAR Cancer, 4(3): zcac026.
• Kuchana V, Kashetti V, Tangeda SJ, Manga V. 2022. Design, synthesis and molecular docking study of thiophenyl hydrazone derivatives as tubulin polymerization inhibitors. Synth Commun, 52(21): 2029-2047.
• Lynch C, Mackowiak B, Huang R, Li L, Heyward S, Sakamuru S, Xia M. 2019. Identification of modulators that activate the constitutive androstane receptor from the Tox21 10K compound library. Toxicol Sci, 167(1): 282-292.
• Macpherson IR, Poondru S, Simon GR, Gedrich R, Brock K, Hopkins CA, Evans TRJ. 2013. A phase 1 study of OSI-930 in combination with erlotinib in patients with advanced solid tumours. Eur J Cancer, 49(4): 782-789.
• Madhavi Sastry G, Adzhigirey M, Day T, Annabhimoju R, Sherman W. 2013. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des, 27: 221-234.
• Martyna GJ, Tobias DJ, Klein ML. 1994. Constant pressure molecular dynamics algorithms. J Chem Phys, 101(5): 4177-4189.
• Masuda T, Tsuruda Y, Matsumoto Y, Uchida H, Nakayama KI, Mimori K. 2020. Drug repositioning in cancer: The current situation in Japan. Cancer Sci, 111(4): 1039-1046.
• Muegge I, Rarey M. 2001. Small molecule docking and scoring. Rev Comput Chem, 17: 1-60.
• Nasab RR, Mansourian M, Hassanzadeh F, Shahlaei M. 2018. Exploring the interaction between epidermal growth factor receptor tyrosine kinase and some of the synthesized inhibitors using combination of in-silico and in-vitro cytotoxicity methods. Res Pharm Sci, 13(6): 509-522.
• Nehra B, Mathew B, Chawla PA. 2022. A medicinal chemist’s perspective towards structure activity relationship of heterocycle based anticancer agents. Curr Top Med Chem, 22(6): 493-528.
• Palanivel S, Yli-Harja O, Kandhavelu M. 2022. Molecular interaction study of novel indoline derivatives with EGFR-kinase domain using multiple computational analysis. J Biomol Struct Dyn, 40(16): 7545-7554.
• Pramesh CS, Badwe RA, Bhoo-Pathy N, Booth CM, Chinnaswamy G, Dare AJ, Gospodarowicz M. 2022. Priorities for cancer research in low-and middle-income countries: a global perspective. Nat Med, 28(4): 649-657.
• Roos K, Wu C, Damm W, Reboul M, Stevenson JM, Lu C, Wang L. 2019. OPLS3e: Extending force field coverage for drug-like small molecules. J Chem Theory Comput, 15(3): 1863-1874.
• Saini N, Grewal AS, Lather V, Gahlawat SK. 2022. Natural alkaloids targeting EGFR in non-small cell lung cancer: Molecular docking and ADMET predictions. Chem Biol Interact, 358: 109901.
• Shaker B, Ahmad S, Lee J, Jung C, Na D. 2021. In silico methods and tools for drug discovery. Comput Biol Med, 137: 104851.
• Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M. 2007. Epik: a software program for pKa prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des, 21: 681-691.
• Sibuh BZ, Gupta PK, Taneja P, Khanna S, Sarkar P, Pachisia S, Singh SK. 2021. Synthesis, in silico study, and anti-cancer activity of thiosemicarbazone derivatives. Biomedicines, 9(10): 1375.
• Siyah P, Durdagi S, Aksoydan B. 2023. Discovery of potential PD-L1 small molecule inhibitors as novel cancer therapeutics using machine learning-based QSAR models: A virtual drug repurposing study. Biophys J, 122(3): 144.
• Stillman NR, Kovacevic M, Balaz I, Hauert S. 2020. In silico modelling of cancer nanomedicine, across scales and transport barriers. NPJ Comput Mater, 6(1): 92.
• Sun M, Wang T, Li L, Li X, Zhai Y, Zhang J, Li W. 2021. The application of inorganic nanoparticles in molecular targeted cancer therapy: EGFR targeting. Front Pharmacol, 12: 702445.
• Tabernero J. 2007. The role of VEGF and EGFR inhibition: implications for combining anti–VEGF and anti–EGFR agents. Mol Cancer Res, 5(3): 203-220.
• Tian X, Gu T, Lee M-H, Dong Z. 2022. Challenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer. Biochim Biophys Acta Rev Cancer, 1877(1): 188645.
• Turanli B, Altay O, Borén J, Turkez H, Nielsen J, Uhlen M, Mardinoglu A. 2021. Systems biology based drug repositioning for development of cancer therapy. Semin Cancer Biol, 68: 47-58.
• Türkmenoğlu B. 2022. Investigation of novel compounds via in silico approaches of EGFR inhibitors as anticancer agents. J Indian Chem Soc, 99(8): 100601.
• Turnham DJ, Bullock N, Dass MS, Staffurth JN, Pearson HB. 2020. The PTEN conundrum: how to target PTEN-deficient prostate cancer. Cells, 9(11): 2342.
• Uribe ML, Marrocco I, Yarden Y. 2021. EGFR in cancer: Signaling mechanisms, drugs, and acquired resistance. Cancers (Basel), 13(11): 2748.
• Vallan L, Istif E, Gómez IJ, Alegret N, Mantione D. 2021. Thiophene-based trimers and their bioapplications: an overview. Polymers (Basel), 13(12): 1977.
• Wang Q, Zeng A, Zhu M, Song L. 2023. Dual inhibition of EGFR VEGF: An effective approach to the treatment of advanced non small cell lung cancer with EGFR mutation. Int J Oncol, 62(2): 1-10.
• Weth FR, Hoggarth GB, Weth AF, Paterson E, White MPJ, Tan ST, Gray C. 2024. Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy. Br J Cancer, 130(5): 703-715.
• Yang X, Hou Z, Wang D, Mou Y, Guo C. 2020. Design, synthesis and biological evaluation of novel heptamethine cyanine dye-erlotinib conjugates as antitumor agents. Bioorg Med Chem Lett, 30(23): 127557.
• Yap TA, Arkenau HT, Camidge DR, George S, Serkova NJ, Gwyther SJ, Desouza NM. 2013. First-in-human phase I trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies. Clin Cancer Res, 19(4): 909-919.
• Zhang L, Lu Z, Zhao X. 2021. Targeting Bcl-2 for cancer therapy. Biochim Biophys Acta Rev Cancer, 1876(1): 188569.
• Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, Ren S. 2011. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol, 12(8): 735-742.