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Identification of natural inhibitors of Bcr‐Abl for the treatment of chronic myeloid leukemia
Author(s) -
Parcha Phanikrishna,
Sarvagalla Sailu,
Madhuri Bindu,
Pajaniradje Sankar,
Baskaran Vinitha,
Coumar Mohane Selvaraj,
Rajasekaran Baskaran
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12983
Subject(s) - myeloid leukemia , abl , cancer research , breakpoint cluster region , chemistry , haematopoiesis , docking (animal) , k562 cells , leukemia , tyrosine kinase , biology , stem cell , gene , signal transduction , biochemistry , microbiology and biotechnology , medicine , immunology , nursing
Chronic myeloid leukemia ( CML ) is a clonal myeloproliferative disorder of the hematopoietic stem cells, characterized at the molecular level by the bcr/abl gene rearrangement. Even though targeting the fusion gene product Bcr‐Abl protein is a successful strategy, development of drug resistance and that of drug intolerance are currently the limitations for Bcr‐Abl‐targeted CML therapy. With an aim to develop natural Bcr‐Abl inhibitors, we performed virtual screening ( VS ) of ZINC natural compound database by docking with Abl kinase using Glide software. Two natural inhibitors ZINC 08764498 (hit1) and ZINC 12891610 (hit2) were selected by considering their high Glide docking score and critical interaction with the hinge region residue Met‐318 of Abl kinase. The reactivity of the two molecules was assessed computationally by density functional theory calculations. Further, the conformational transition, hydrogen bond interactions, and the binding energies were investigated during 10‐ns molecular dynamics simulation of the Abl–hit complex. When tested in vitro, hit1 compared to hit2 showed selective inhibition of cell proliferation and induction of apoptosis in Bcr‐Abl‐positive K‐562 leukemia cells. In summary, our results demonstrate that ZINC 08764498, a coumarin derivative identified through VS , is a potential natural inhibitor for the treatment of CML .