In-Silico Design Of Ponatinib, In Treatment Of CML

In-Silico Design Of Ponatinib, In Treatment Of CML

Protein Kinase Receptors (PKRs) play an important role in cell signalling 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 bysomatic 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.

Introduction

Chronic Myeloid Leukemia(CML) originates from the chromosomal detachment which is the results of reciprocal translocation of the Abelson gene on Chromosome 9 to break point cluster region gene on Chromosome 22, creating fusion oncogene, BCR-ABL (9;22) [1].The fused BCR-ABL protein deregulated tyrosine kinase activity which governs uncontrolled proliferation and it is the main pathology of CML [2,3].Human protein kinases regulates various cellular process such as proliferation, differentiation, death and migration [4]. Small molecules inhibitors can block the activity of protein kinases and dissecting the roles of protein kinases [5]. Kinases have ATP binding pocket n-lobe, c-lobeand connecting hing region and most kinases inhibitors exert their activity binding through this region [6].Type-I kinase inhibitors show Asp-phe-Gly (DFG)-in and type-II kinase inhibitors show DFG-out binding [7]. BCR-ABL was the first kinase against which small molecule inhibitor was successfully approved [8].The five BCR-ABL inhibitors are: Imatinib (1st generation), Dosatinib, Nilotinib, Bosutinib (2nd generation),and Ponatinib(3rd generation).The four BCR-ABL kinase inhibitors except Ponatinib experienced with various resistance and T315I mutation is a unique mutation in casae of all these four drug [9]. This mutation is the cause of replacement of wild-type threonine at ABL residue 315 with an isoleucine which termed as T315I or gatekeeper mutation [10]. Ponatinib is the third generation kinase inhibitor designed to overcome T315I mutation [11].

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