Resistance to the drug crizotinib due to the mutation of its target protein, Anaplastic Lymphoma Kinase (ALK) is a significant drawback for treatment of patients suffering from lung cancer. The aim of the study was to identify a drug compound which is structurally, physiologically and functionally similar to crizotinib which will act as a replacement in lung cancer therapy. Structural alignment was performed to gain greater perspective wherein the Z-scores and RMSD values reveal drug molecules of significant similarity to crizotinib. Pharmacophore analysis was performed using an online webserver called PharmaGist to compare the pharmacophores of data set drugs to the pharmacophore of crizotinib. The structural and physiological similarity were investigated using ChemMine and to generate similarity indices between crizotinib and the test molecules. Binding energy studies were performed using Autodock 4.0 to filter out drug molecules which are chosen such that the binding energy corresponding to the mutant ALK is less negative than that of native ALK. The number of clusters forms and the number of hydrogen bonds were also kept in mind while choosing the molecules. The required molecule was identified after strict analysis and filtering procedures, providing a replacement drug molecule for improved therapeutic use.
Cite this article:
Muniyan Rajiniraja. Prediction of alternate drugs for Crizotinib resistant mutated-ALK inhibitors in lung cancer treatment: An In silico approach. Research J. Pharm. and Tech. 2020; 13(8):3643-3647. doi: 10.5958/0974-360X.2020.00644.7
1. Robin MJM van Geel, Jeroen JMA Hendrikx, Jelmer E Vahl, Monique E van Leerdam, Daan van den Broek, Alwin DR Huitema, Jos H Beijnen, Jan HM Schellens, Sjaak A Burgers. (2016). Crizotinib-induced fatal fulminant liver failure. Lung Cancer, 93, 17-19.
2. Daniela Iacono, Rita Chiaria. (2015). Future options for ALK-positive non-small cell lung cancer. Lung Cancer. 87, 211–219.
3. Maximilian von Laffert, Albrecht Stenzinger, Michael Hummel, Wilko Weichert, Dido Lenze, Arne Warth, Roland Penzel, Hermann Herbst, Udo Kellner, Philipp Jurmeister, Peter Schirmacher, Manfred Dietel, Frederick Klauschen. (2015). ALK-FISH borderline cases in non-small cell lung cancer: Implications for diagnostics and clinical decision making. Lung Cancer, 90, 465–471.
4. Federico Cappuzzoa, Denis Moro-Sibilot. (2015). Management of crizotinib therapy for ALK-rearranged non-small celllung carcinoma: An expert consensus. Lung Cancer, 87, 89–95.
5. Giorgio Scagliotti, Rolf A Stahel. (2012). ALK translocation and crizotinib in non-small cell lung cancer: An evolving paradigm in oncology drug development. Eur J Cancer, 48, 961– 973.
6. Fiona Blackhall, Dong-Wan Kim. Patient-Reported Outcomes and Quality of Life in PROFILE1007: A Randomized Trial of Crizotinib Compared with Chemotherapy in Previously Treated Patients with ALK-Positive Advanced Non–Small-Cell Lung Cancer. (2014). J Thorac Oncol., 9, 1625-1633.
7. Maria Cecilia Mengolia, Fausto Barbieri, Federica Bertolini, Marcello Tiseo, Giulio Rossia. (2016). K-RAS mutations indicating primary resistance to crizotinib in ALK-rearranged adenocarcinomas of the lung: Report of two cases and review of the literature. Lung Cancer, 93,55–58.
8. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. (2006). Drug Bank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res., 34, 668-672.
9. Cui JJ, Tran-Dube M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, Mctigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP. (2011). Structure Based Drug Design of Crizotinib (Pf-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (C-met) Kinase and Anaplastic Lymphoma Kinase (Alk). J Med Chem. 54, 6342 - 6363.
10. HM Berman, J Westbrook, Z Feng, G Gilliland, TN Bhat, H Weissig, IN Shindyalov, PE Bourne. (2000). The Protein Data Bank. Nucleic Acids Res. 28, 235-242.
11. Golan Yona. (2011). In: Introduction to Computational Proteomics. Chapman and Hill Publishing. Pp 291 – 340.
12. Schneidman-Duhovny D, Dror O, Inbar Y, Nussinov R, Wolfson HJ. (2008). Pharma Gist: a webserver for ligand-based pharmacophore detection. Nucleic Acids Res., 36, 223 – 228.
13. NM O'Boyle, M Banck, CA James, C Morley, T Vandermeersch, GR Hutchison. (2011). Open Babel: An open chemical toolbox. J Cheminform., 3,33.
14. Backman T, Cao Y, Girke T. (2011).ChemMine Tools: an online service for analyzing and clustering small molecules. Nucleic Acids Res., 39, 486–491.
15. Chen X, Reynolds CH. (2002). Performance of similarity measure in 2D fragment-based similarity searching: comparison of structural descriptors and similarity coefficients. J Chem Inf Comput Sci., 42,1407-1414.
16. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ. (1998). Automated Docking Using a Lamarckian Genetic Algorithm.J Comput Chem. 19,1639-1662.
17. R Priya, Rajendrarao Sumitha, C George Priya Doss, C Rajasekaran, S Babu, R Seenivasan, R Siva. (2015). Molecular Docking and Molecular Dynamics to Identify a Novel Human Immunodeficiency Virus Inhibitor from Alkaloids of Toddalia asiatica. Pharmacogn Mag., 11, 414–422.
18. Baul, H. S. and Rajiniraja M. (2018). Molecular Docking Studies of Selected Flavonoids on Inducible Nitric Oxide Synthase (iNOS) in Parkinson’s Disease. Research Journal of Pharmacy and Technology.11, 3685.
19. Wallace AC, Laskowski RA, Thornton JM. (1995). LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Prot Eng., 8, 127-134.