IN-SILICO DESIGN OF PONATINIB, IN TREATMENT OF CML

Abul Bashar Ripon Khalipha1,2*, Bilkis Khanom1, Md. Solayman Hossain1, Muhammad Torequl Islam1, Thoufiqul Alam Riaz3

1Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh.

2Evergreen Scientific Research Centre, Gopalganj-8100, Bangladesh

3Department of Pharmacology and Institute of New Drug Development, Jeonbuk National University Medical School, 54907, Jeonju, Republic of Korea

Abstract: Protein Kinase Receptors (PKRs) play an important role in cell signaling processes which regulate cell growth and proliferation and for this PKRs are the major target of anti-cancer therapies. BCR-ABL is kinase protein responsible for Chronic Myeloid Leukemia (CML) and there are five approved drug to treat CML. Recently it has been shown that the second generation BCR-ABL inhibitor nilotinib has weak-off target activity against RAF proto-oncogene serine-threonine-protein kinase, (BRAF, CRAF). BRAF is serine/threonine protein kinase, commonly activated by somatic point mutation in human cancer which may provide new therapeutic advantages in malignant cancer. Ponatinib is third generation BCR-ABL tyrosine kinase inhibitor, effective against T315I mutation and some other kinases. Using virtual screening approach and molecular docking, here we examined the activity of Ponatinib and some of its analogs against BRAF (6CAD). Docking was performed among various proteins (6CAD, 5FLF, 2XYN, 4LUD, 4RWK, 4YC8) and the parent drug as well as all the analogs to assess the binding affinity and non-bond interaction. From the docked results it was estimated that with 6CAD, analog having trichloro-methyl group at N3 position of parent structure exerts lowest binding affinity -10.1 Kcal/mol and analog having mono-chloro-di-fluoro methyl group at C19 position of parent structure exerts the best binding affinity -12.3Kcal/mol compared to the binding affinity -11.9 Kcal/mol of the parent drug which contains trifluoromethyl group at C19 position. Frontier HOMO-LUMO was calculated to assess their chemical reactivity. Pharmacokinetic parameters are studied by using a software to evaluate the drug property considering absorption, metabolism and toxicity of the compounds.This study can be useful for the development of new therapeutic agent against Serine/threonine kinase 6CAD which is the signaling protein for CML.

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