Identification of natural inhibitors of Bcr-Abl for the treatment of chronic myeloid leukemia.
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.
Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, India.|DBT-Interdisciplinary Program in Life Sciences, School of Life Sciences, Pondicherry University, Puducherry, India.
Phanikrishna
P
Parcha
Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India.
Sailu
S
Sarvagalla
DBT-Interdisciplinary Program in Life Sciences, School of Life Sciences, Pondicherry University, Puducherry, India.|Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry, India.
Bindu
B
Madhuri
Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, India.
Sankar
S
Pajaniradje
Department of Medicine and Health Sciences, SRM University, Kattankulathur, Chennai, India.
Vinitha
V
Baskaran
DBT-Interdisciplinary Program in Life Sciences, School of Life Sciences, Pondicherry University, Puducherry, India.|Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India.
Mohane Selvaraj
MS
Coumar
Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, India.|DBT-Interdisciplinary Program in Life Sciences, School of Life Sciences, Pondicherry University, Puducherry, India.
Baskaran
http://orcid.org/0000-0002-0441-0723
B
Rajasekaran
D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
D001688:Biological Products; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl
Bcr-Abl; density functional theory; in vitro testing; molecular dynamics simulations; virtual screening