Identification of Dual Natural Inhibitors for Chronic Myeloid Leukemia by Virtual Screening, Molecular Dynamics Simulation and ADMET Analysis

• Published in: Interdisciplinary sciences : computational life sciences 2016-09, Vol.8 (3), p.241-252
• Main Authors: Kumar, Himansu, Raj, Utkarsh, Srivastava, Swati, Gupta, Saurabh, Varadwaj, Pritish K.
• Format: Article
• Language: English
• Subjects: Aberration; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; BCR-ABL protein; Binding; Biomedical and Life Sciences; Bone marrow; Chronic myeloid leukemia; Computational Biology - methods; Computational Biology/Bioinformatics; Computational Science and Engineering; Computer Appl. in Life Sciences; Computer simulation; Coordination compounds; Dasatinib - chemistry; Dasatinib - therapeutic use; Disease control; Docking; Drugs; Fusion protein; Health Sciences; Humans; Imatinib; Imatinib Mesylate - chemistry; Imatinib Mesylate - therapeutic use; Inhibitors; Leukemia; Leukemia, Myeloid - drug therapy; Leukemias; Leukocytes (granulocytic); Life Sciences; Mathematical and Computational Physics; Medicine; Molecular dynamics; Molecular Dynamics Simulation; Myeloid leukemia; Original Research Article; Protein-tyrosine kinase; Proteins; Receptors; Screening; Stability analysis; Statistics for Life Sciences; Stem cells; Theoretical; Theoretical and Computational Chemistry; Tyrosine
• ISSN: 1913-2751; 1867-1462
• DOI: 10.1007/s12539-015-0118-7

Chronic myeloid leukemia (CML) is a disease of bone marrow stem cells caused by excessive growth and accumulation of granulocytes in the blood. Aberrant expression of the BCR-ABL proteins in bone marrow stem cells have found out in 95 % cases of CML. Tyrosine Kinase domains (SH2 and SH3) of BCR-ABL proteins are the potent targets to inhibit the process. Initially, imatinib is preferred as an efficient inhibitor to control functional activity of disease. Recently, it has been reported that the advanced stage of CML developed resistance against imatinib. In continuation, dasatinib is the first drug to combat against this disease by targeting multiple receptors and proven better as compared to imatinib. Here, an attempt has been made to identify similar analogs of dasatinib. Virtual screening was performed against various natural compound databases to get some potent natural compounds which are able to inhibit more than one receptor. Binding affinity of screened natural compounds was compared with some of the well-known inhibitors like imatinib, dasatinib, nilotinib etc., by analyzing their docking score and binding efficiency with the receptor. Stability of the best ligand–receptor complex was checked by performing 10 ns molecular dynamics simulation. ADMET properties of the obtained screened compounds were analyzed to check drug like property. Based on the aforementioned analysis, it has been suggested that these screened potent compounds are capable to inhibit multiple receptor proteins like ABL and SRC and consequently combat against the deadly disease CML.