Author(s):
Prangya Parimita Panda, Abhijit Saha
Email(s):
abh.sah2@gmail.com
DOI:
10.52711/0974-360X.2026.00111 
Address:
Prangya Parimita Panda1, Abhijit Saha2*
1Biotechnology Department, College of Pharmaceutical Sciences, Mohuda, Berhampur, Odisha, Pin - 760002, India.
2Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Durgapur, West Bengal, Pin-713206, India.
*Corresponding Author
Published In:
Volume - 19,
Issue - 2,
Year - 2026
ABSTRACT:
Gefitinib (ZD1839) a selective EGFR inhibitor approved by the FDA is used to treat metastatic non-small cell lung cancer in humans. So, screening compounds having similar pharmacophoric features like Gefitinib with multi targeted effect to restrict drug resistance is the main motivation of this work. A pharmacophore was generated from the crystal structure of Gefitinib-EGFR complex with several pharmacophoric features. May Bridge database contains 51,663 drug like compounds were taken for virtual screening and according to the Fit value best hit compound (Hit-1) was chosen for lead optimization to improve pharmacophoric features. Optimized Leads were further screened with same pharmacophoric features of Gefitinib-EGFR complex to obtained better Hit compounds i.e. methyl 2-((7-methoxy-6-(3-(piperazin-1-yl) propoxy) quinazolin-4-yl) thio) acetate (Hit-2) and compound methyl 2-((7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-yl) thio) acetate (Hit-3) with high Fit value (4.83269 and 4.76094). Finally, their ADMET prediction and binding study with EGFR and VEGFR-2 were performed to conclude multitargeted effect.
Cite this article:
Prangya Parimita Panda, Abhijit Saha. Pharmacophore Based Design and Development of Probable Multi Tyrosine Kinase Inhibitors from the 3D Crystal Structure of Gefitinib – A Drug Used in the Treatment of NSCLC. Research Journal of Pharmacy and Technology. 2026;19(2):772-9. doi: 10.52711/0974-360X.2026.00111
Cite(Electronic):
Prangya Parimita Panda, Abhijit Saha. Pharmacophore Based Design and Development of Probable Multi Tyrosine Kinase Inhibitors from the 3D Crystal Structure of Gefitinib – A Drug Used in the Treatment of NSCLC. Research Journal of Pharmacy and Technology. 2026;19(2):772-9. doi: 10.52711/0974-360X.2026.00111 Available on: https://rjptonline.org/AbstractView.aspx?PID=2026-19-2-40
REFERENCES:
1. Nagano T, Tachihara M, Nishimura Y. Molecular Mechanisms and Targeted Therapies Including Immunotherapy for Non-Small Cell Lung Cancer. Current Cancer Drug Targets. 2019; 19(8): 595-630. doi:10.2174/1568009619666181210114559
2. Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nature Reviews Cancer. 2014; 14(8): 535-546. doi:10.1038/nrc3775
3. Board PC. BRCA1 and BRCA2: Cancer Risks and Management (PDQ®). InPDQ Cancer Information Summaries [Internet] 2023. National Cancer Institute (US).
4. Nag MK, Patel S, Panik R, Shrivastava S, Daharwal SJ, Singh MR, Singh D. Lung cancer targeting: a review. Research Journal of Pharmacy and Technology. 2013; 6(11): 1302-1306.
5. Sari S, Andayani TM, Endarti D, Widayati K. Health-related quality of life in non-small cell lung cancer (NSCLC) patients with mutation of epidermal growth factor receptor (EGFR) in Indonesia. Research Journal of Pharmacy and Technology. 2020; 13(1): 443-447.
6. Shukla Maitri Jayeshkumar, Patel Yashvi, Bhavin Bhimani, Ghanshyam Patel, Jaimin Patel, Upendra Patel. Nebulization Therapy for Lung Cancer. Research Journal of Pharmacy and Technology. 2019; 12(2): 920-934. doi: 10.5958/0974-360X.2019.00157.4
7. Sindhu PS, Ramamurthy B. Lung Cancer Detection using Image Processing Technique. Research Journal of Pharmacy and Technology. 2018; 11(5): 2045-2049. doi: 10.5958/0974-360X.2018.00379.7
8. Yao Y, Fareed R, Zafar A, Saleem K, Huang T, Duan Y, Rehman MU. State-of-the-art combination treatment strategies for advanced stage non–small cell lung cancer. Frontiers in Oncology. 2022; 12: 958505. https://doi.org/10.3389/fonc.2022.958505
9. Sari S, Andayani TM, Endarti D, Widayati K. Cost-effectiveness analysis of afatinib versus gefitinib in non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation in Indonesia: observational studies with retrospectives. Research Journal of Pharmacy and Technology. 2022; 15(4): 1598-1602.doi: 10.52711/0974-360X.2022.00267
10. Liu TC, Jin X, Wang Y, Wang K. Role of epidermal growth factor receptor in lung cancer and targeted therapies. American Journal of Cancer Research. 2017; 7(2): 187.
11. Carcereny E, Morán T, Capdevila L, Cros S, Vilà L, de los Llanos Gil M, Remón J, Rosell R. The epidermal growth factor receptor (EGRF) in lung cancer. Translational Respiratory Medicine. 2015; 3: 1-8. https://doi.org/10.1186/s40247-015-0013-z
12. Marmor MD, Skaria KB, Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors. International Journal of Radiation Oncology Biology Physics. 2004; 58(3): 903-913. https://doi.org/10.1016/j.ijrobp.2003.06.002
13. Padmapriya A, Preetha S, Selvaraj J, Sridevi G. Effect of Carica papaya seed extract on IL -6 and TNF-α in human lung cancer cell lines - an In vitro study. Research Journal of Pharmacy and Technology. 2022; 15(12): 5478-5482. doi: 10.52711/0974-360X.2022.00924
14. Morabito A, Carillio G, Daniele G, Piccirillo MC, Montanino A, Costanzo R, Sandomenico C, Giordano P, Normanno N, Perrone F, Rocco G. Treatment of small cell lung cancer. Critical Reviews in Oncology/Hematology. 2014;91(3):257-270.
15. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014; 25(3): 282-303.
16. Muniyan R. Prediction of alternate drugs for Crizotinib resistant mutated-ALK inhibitors in lung cancer treatment: An In silico approach. Research Journal of Pharmacy and Technology. 2020; 13(8): 3643- 3647. doi: 10.5958/0974-360X.2020.00644.7
17. Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008; 65(10): 1566-1584. doi: 10.1007/s00018-008-7440-8.
18. Le Dinh Chac, Bui Bao Thinh, Nguyen Thi Yen. Anti-cancer activity of dry extract of Anoectochilus setaceus Blume against BT474 breast cancer cell line and A549 lung cancer cell line. Research Journal of Pharmacy and Technology. 2021; 14(2): 730-734. doi: 10.5958/0974-360X.2021.00127.X
19. Gayathri K, Vaidhehi V. An Automatic Identification of Lung Cancer from different types of Medical Images. Research Journal of Pharmacy and Technology. 2019; 12(5): 2109-2115. doi: 10.5958/0974-360X.2019.00350.0
20. Gou HF, Li X, Qiu M, Cheng K, Li LH, Dong H, Chen Y, Tang Y, Gao F, Zhao F, Men HT, Ge J, Su JM, Xu F, Bi F, Gao JJ, Liu JY. Epidermal growth factor receptor (EGFR)-RAS signaling pathway in penile squamous cell carcinoma. PLoS One. 2013; 8(4): e62175. doi: 10.1371/journal.pone.0062175.
21. Devgun M, Singh L, Sharma S. Structure prediction and In-silico designing of drugs against plant homeodomain finger protein 14 for suppression of malignant transformation and tumorigenicity of non small cell lung cancer. Research Journal of Pharmacy and Technology. 2022; 15(10): 4621-4626. doi: 10.52711/0974-360X.2022.00775
22. Oxnard GR, Miller VA. Use of erlotinib or gefitinib as initial therapy in advanced NSCLC. Oncology (Williston Park). 2010; 24(5): 392-399.
23. Kuykendall A, Chiappori A. Advanced EGFR mutation-positive non-small-cell lung cancer: case report, literature review, and treatment recommendations. Cancer Control. 2014; 21(1): 67-73. doi: 10.1177/107327481402100110.
24. Kazandjian D, Blumenthal GM, Yuan W, He K, Keegan P, Pazdur R. FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer. Clinical Cancer Research. 2016; 15; 22(6): 1307-1312. doi: 10.1158/1078-0432.
25. Hanna N, Lilenbaum R, Ansari R, Lynch T, Govindan R, Jänne PA, Bonomi P. Phase II trial of cetuximab in patients with previously treated non–small-cell lung cancer. Journal of Clinical Oncology. 2006; 24(33): 5253-5258. doi: 10.1200/JCO.2006.08.2263.
26. Robert F, Blumenschein G, Herbst RS, Fossella FV, Tseng J, Saleh MN, Needle M. Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. Journal of Clinical Oncology. 2005; 23(36): 9089-9096. doi: 10.1200/JCO.2004.00.1438.
27. Langer CJ. Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. International Journal of Radiation Oncology Biology Physics. 2004; 58(3): 991-1002.
28. de Marinis F, Pereira JR, Fossella F, Perry MC, Reck M, Salzberg M, Jassem J, Peterson P, Liepa AM, Moore P, Gralla RJ. Lung Cancer Symptom Scale outcomes in relation to standard efficacy measures: an analysis of the phase III study of pemetrexed versus docetaxel in advanced non-small cell lung cancer. Journal of Thoracic Oncology. 2008; 3(1): 30-36. doi: 10.1097/JTO.0b013e31815e8b48.
29. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. New England Journal of Medicine. 2005; 352(8): 786-792. doi: 10.1056/NEJMoa044238.
30. Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG, Halmos B. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Research. 2005; 65(16): 7096-7101. doi: 10.1158/0008-5472.
31. Dassault Systèmes BIOVIA, Discovery Studio, 4.1, San Diego: Dassault Systèmes, 2017.
32. Chemical Structure Drawing Standard, Cambridge Soft Corporation, USA, 2010.
33. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017; 7: 42717. doi: 10.1038/srep42717.
34. RCSB Protein Data Bank, “RCSB PDB: Homepage,” Rcsb.org. [Online]. https://www.rcsb.org/
35. Arooj M, Sakkiah S, Kim S, Arulalapperumal V, Lee KW. A combination of receptor-based pharmacophore modeling & QM techniques for identification of human chymase inhibitors. PLoS One. 2013; 8(4): e63030. doi: 10.1371/journal.pone.0063030.
36. Wolber G, Langer T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. Journal of Chemical Information and Modeling. 2005; 45(1): 160-169. doi: 10.1021/ci049885e.
37. Jin B, Hopfinger AJ. A proposed common spatial pharmacophore and the corresponding active conformations of some TxA2 receptor antagonists. Journal of Chemical Information and Computer Sciences 1994; 34(4): 1014-1021. doi: 10.1021/ci00020a041.
38. Yang J, Wang D, Jia C, Wang M, Hao G, Yang G. Freely Accessible Chemical Database Resources of Compounds for In Silico Drug Discovery. Current Medicinal Chemistry. 2019; 26(42): 7581-7597. doi: 10.2174/0929867325666180508100436.
39. http://www.maybridge.com
40. Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today Technology. 2004; 1(4): 337-341. doi: 10.1016/j.ddtec.2004.11.007.
41. Pal S, Kumar V, Kundu B, Bhattacharya D, Preethy N, Reddy MP, Talukdar A. Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential Topoisomerase I Inhibitors. Computational and Structural Biotechnology Journal. 2019;17:291-310. doi: 10.1016/j.csbj.2019.02.006.
42. Joseph-McCarthy D, Baber JC, Feyfant E, Thompson DC, Humblet C. Lead optimization via high-throughput molecular docking. Current Opinion in Drug Discovery & Development. 2007; 10(3): 264-274.
43. Diller DJ, Merz Jr KM. High throughput docking for library design and library prioritization. Proteins: Structure, Function, and Bioinformatics. 2001; 43(2): 113-124.
44. Kristam R, Gillet VJ, Lewis RA, Thorner D. Comparison of conformational analysis techniques to generate pharmacophore hypotheses using catalyst. Journal of Chemical Information and Modeling. 2005; 45(2): 461-476. doi: 10.1021/ci049731z.
45. Brooks BR, Brooks CL 3rd, Mackerell AD Jr, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M. CHARMM: the biomolecular simulation program. Journal of Computational Chemistry. 2009; 30(10): 1545-1614. doi: 10.1002/jcc.21287.
46. Atkovska K, Samsonov SA, Paszkowski-Rogacz M, Pisabarro MT. Multipose binding in molecular docking. International Journal of Molecular Sciences. 2014; 15(2): 2622-2645. doi: 10.3390/ijms15022622.
47. Cavasotto CN. Binding free energy calculation using quantum mechanics aimed for drug lead optimization. Quantum Mechanics in Drug Discovery. 2020:257-268.
48. Sarker K, Ghosh A, Saha A, Mishra S, Sen S. Pharmacophore Based Design of Probable FGFR-1 Inhibitors from the 3D Crystal Structure of Infigratinib-A Drug Used in the Treatment of Cholangiocarcinomas. Letters in Drug Design & Discovery. 2022; 19(4): 314-322.
49. Zhang G, Guo S, Cui H, Qi J. Virtual Screening of Small Molecular Inhibitors against DprE1. Molecules. 2018; 23(3): 524. doi: 10.3390/molecules23030524.