Nilotinib based pharmacophore models for BCRABL

Tyrosine kinase inhibitors have revolutionized the treatment of several malignancies, converting lethal diseases in a manageableaspect. Imitanib, a small molecule ABL kinase inhibitor is a highly effective therapy for early phase chronic myeloid leukemia(CML), which has constitutively active ABL kinase activity owing to the over expression of the BCR-ABL fusion protein. But somepatients develop imatinib resistance, particularly in the advanced phases of CML.The discovery of resistance mechanisms ofimitanib; urge forward the development of second generation drugs. Nilotinib, a second generation drug is more potent inhibitorof BCR-ABL than imatinib. But nilotinib also develops dermatologic events and headache in patients. Large information aboutBCR-ABL structure and its inhibitors are now available. Based on the pharmacophore modeling approaches, it is possible todecipher the molecular determinants to inhibit BCR-ABL. We conducted a structure based and ligand based study to identifypotent natural compounds as BCR-ABL inhibitor. First kinase inhibitors were docked with the receptor (BCR-ABL) and nilotinibwas selected as a pharmacophore due its high binding efficiency. Eleven compounds were selected out of 1457 substances whichhave mutual pharmacopohre features with nilotinib. These eleven compounds were validated and used for docking study to findthe drug like molecules. The best molecules from the final set of screening candidates can be evaluated in cell lines and mayrepresent a novel class of BCR-ABL inhibitors.

Abbreviations

CML - Chronic myeloid leukemia, PDGFR - Platelet derived growth factor receptor, TKI - Tyrosine kinase inhibitors.