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Identification and Pharmacological Analysis of High Efficacy Small Molecule Inhibitors of EGF-EGFR Interactions in Clinical Treatment of Non-Small Cell Lung Carcinoma: a Computational Approach

  • Gudala, Suresh (Institute of Genetics and Hospital for Genetic Diseases, Osmania University) ;
  • Khan, Uzma (In silico Research Laboratory, Eminent Biosciences) ;
  • Kanungo, Niteesh (In silico Research Laboratory, Eminent Biosciences) ;
  • Bandaru, Srinivas (Institute of Genetics and Hospital for Genetic Diseases, Osmania University) ;
  • Hussain, Tajamul (Center of Excellence in Biotechnology Research, College of Science, King Saud University) ;
  • Parihar, MS (School of Studies in Zoology & Biotechnology, Vikram University) ;
  • Nayarisseri, Anuraj (In silico Research Laboratory, Eminent Biosciences) ;
  • Mundluru, Hema Prasad (Institute of Genetics and Hospital for Genetic Diseases, Osmania University)
  • Published : 2016.01.11

Abstract

Inhibition of EGFR-EGF interactions forms an important therapeutic rationale in treatment of non-small cell lung carcinoma. Established inhibitors have been successful in reducing proliferative processes observed in NSCLC, however patients suffer serious side effects. Considering the narrow therapeutic window of present EGFR inhibitors, the present study centred on identifying high efficacy EGFR inhibitors through structure based virtual screening strategies. Established inhibitors - Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib formed parent compounds to retrieve similar compounds by linear fingerprint based tanimoto search with a threshold of 90%. The compounds (parents and respective similars) were docked at the EGF binding cleft of EGFR. Patch dock supervised protein-protein interactions were established between EGF and ligand (query and similar) bound and free states of EGFR. Compounds ADS103317, AKOS024836912, AGN-PC-0MXVWT, GNF-Pf-3539, SCHEMBL15205939 were retrieved respectively similar to Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib. Compound-AGN-PC-0MXVWT akin to Erlotinib showed highest affinity against EGFR amongst all the compounds (parent and similar) assessed in the study. Further, AGN-PC-0MXVWT brought about significant blocking of EGFR-EGF interactions in addition showed appreciable ADMET properties and pharmacophoric features. In the study, we report AGN-PC-0MXVWT to be an efficient and high efficacy inhibitor of EGFR-EGF interactions identified through computational approaches.

Keywords

Non-small cell lung carcinoma;EGFR inhibitors;molecular docking;virtual screening

Acknowledgement

Supported by : Rajiv Gandhi National Fellowship Scheme (RGNF)

References

  1. Ahmad S, Gromiha M, Fawareh H, Sarai A (2004). ASAView: database and tool for solvent accessibility representation in proteins. BMC Bioinformatics, 5, 824-27.
  2. Bandaru S, Tiwari G, Akka J, et al (2015). Identification of high affinity bioactive salbutamol conformer directed against mutated (Thr164Ile) Beta 2 adrenergic receptor. Cur Top Med Chem, 15, 50-56. https://doi.org/10.2174/1568026615666150112113040
  3. Basse MJ, Betzi S, Bourgeas R, et al (2013). 2P2Idb: a structural database dedicated to orthosteric modulation of proteinprotein interactions. Nucleic Acids Res, 41, 824-27. https://doi.org/10.1093/nar/gks1002
  4. Blume-Jensen P, Hunter T (2001). Oncogenic kinase signalling. Nature, 411, 355-65. https://doi.org/10.1038/35077225
  5. Cheng F, Li W, Zhou Y, et al (2012). admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J chem inf and model, 52, 3099-105. https://doi.org/10.1021/ci300367a
  6. Dahabreh IJ, Terasawa T, Castaldi PJ, et al (2011). Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Annal Inter Med, 154, 37-49. https://doi.org/10.7326/0003-4819-154-1-201101040-00006
  7. Ferguson KM, Berger MB, Mendrola JM, et al (2003). EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Molecular Cell, 11, 507-17. https://doi.org/10.1016/S1097-2765(03)00047-9
  8. Ferlay J, Shin HR, Bray F, et al (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Caner, 127, 2893-917. https://doi.org/10.1002/ijc.25516
  9. Govindan R, Page N, Morgensztern D, et al (2006). Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol, 24, 4539-44. https://doi.org/10.1200/JCO.2005.04.4859
  10. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  11. Jemal A, Siegel R, Xu J, (2010). Cancer Statistics. CA Cancer J Clin, 60, 277-300. https://doi.org/10.3322/caac.20073
  12. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996). Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc, 118, 11225-36. https://doi.org/10.1021/ja9621760
  13. Lacouture M, Basti S, Patel J, et al (2006). The SERIES Clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol, 4, 236-8.
  14. Lacouture ME, Maitland ML, Segaert S, et al (2010). A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Support Care Cancer, 18, 509-22. https://doi.org/10.1007/s00520-009-0744-x
  15. LigPrep, V. (2010). 2.4, Schrodinger. LLC, New York.
  16. Lynch TJ, Kim ES, Eaby B, et al (2007). Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist, 12, 610-21. https://doi.org/10.1634/theoncologist.12-5-610
  17. Marino P, Pampallona S, Preatoni A, et al (1994). Chemotherapy vs supportive care in advanced non-smallcell lung cancer. Results of a meta-analysis of the literature. Chest, 106, 861-5. https://doi.org/10.1378/chest.106.3.861
  18. Nelder JA, Mead R (1965). A simplex method for function minimization. The comput J, 7, 308-13. https://doi.org/10.1093/comjnl/7.4.308
  19. Pirker R, Pereira JR, Szczesna A, et al (2009). Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet, 373, 1525-31. https://doi.org/10.1016/S0140-6736(09)60569-9
  20. Reichmann D, Phillip Y, Carmi A, Schreiber G (2008). On the contribution of water-mediated interactions to proteincomplex stability. Biochemistry, 47, 1051-60. https://doi.org/10.1021/bi7019639
  21. Schiller JH, Harrington D, Belani CP, et al (2002). Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 346, 92-8. https://doi.org/10.1056/NEJMoa011954
  22. Schneidman-Duhovny D, Inbar Y, Nussinov R, et al (2005). PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res, 33, 363-7 https://doi.org/10.1093/nar/gki481
  23. Stinchcombe TE, Bradford DS, Hensing TA, et al (2010). A multicenter phase II trial of carboplatin and cetuximab for treatment of advanced non small cell lung cancer. Cancer Invest, 28, 208-15.
  24. Takiar R, Nadayil D, Nandakumar A (2010). Projections of number of cancer cases in India (2010-2020) by cancer groups. Asian Pac J Cancer Prev, 11, 1045-49.
  25. Thatcher N, Chang A, Parikh P, et al (2005). Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 366, 1527-37. https://doi.org/10.1016/S0140-6736(05)67625-8
  26. Ullrich A, Schlessinger J (1990). Signal transduction by receptors with tyrosine kinase activity. Cell, 61, 203-212. https://doi.org/10.1016/0092-8674(90)90801-K
  27. Usuda K, Sagawa M, Motono N, et al (2013). Relationships between EGFR mutation status of lung cancer and preoperative factors-are they predictive? Asian Pac J Cancer Prev, 15, 657-62.
  28. Wang YS, Wang YH, Xia H, et al (2012). MicroRNA-214 regulates the acquired resistance to gefitinib via the PTEN/ AKT pathway in EGFR-mutant cell lines. Asian Pac J Cancer Prev, 13, 255-60. https://doi.org/10.7314/APJCP.2012.13.1.255
  29. Yang JM, Chen CC (2004). Gemdock: A generic evolutionary method for molecular docking. Proteins, 55, 288-304 https://doi.org/10.1002/prot.20035
  30. Yang ZY, Liu L, Mao C, et al (2014). Chemotherapy with cetuximab versus chemotherapy alone for chemotherapy naive advanced non small cell lung cancer. Cochrane Database Syst Rev, 11, 9948.