3 years ago

Identification of natural inhibitors of Bcr-Abl for the treatment of chronic myeloid leukemia

Identification of natural inhibitors of Bcr-Abl for the treatment of chronic myeloid leukemia
Mohane Selvaraj Coumar, Vinitha Baskaran, Sailu Sarvagalla, Phanikrishna Parcha, Bindu Madhuri, Baskaran Rajasekaran, Sankar Pajaniradje
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 ZINC08764498 (hit1) and ZINC12891610 (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 ZINC08764498, a coumarin derivative identified through VS, is a potential natural inhibitor for the treatment of CML. In this study, we performed virtual screening of ZINC natural compounds by docking to the Abl kinase ATP-binding site using Glide software. Two natural inhibitors ZINC08764498 (hit1) and ZINC12891610 (hit2) were selected by considering their high Glide docking score and stable interaction with the hinge region residue Met-318 of Abl kinase catalytic domain. The compounds were further validated using density functional theory and 10-ns molecular dynamic simulations. In vitro testing results showed that compound ZINC08764498 (hit1) has selective pro-apoptotic activity on Bcr-Abl-overexpressing K-562 cells and no significant cytotoxicity on Bcr-Abl-negative HEK-293 cell line.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12983

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