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Updated: May 17, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Nilotinib based pharmacophore models for BCRABL
1Department of Bioinformatics, Guru Nanak College, Velacherry, Chennai-600 036.
Unlabelled:
Tyrosine kinase inhibitors have revolutionized the treatment of several malignancies, converting lethal diseases in a manageable aspect. 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 some patients develop imatinib resistance, particularly in the advanced phases of CML.The discovery of resistance mechanisms of imitanib; urge forward the development of second generation drugs. Nilotinib, a second generation drug is more potent inhibitor of BCR-ABL than imatinib. But nilotinib also develops dermatologic events and headache in patients. Large information about BCR-ABL structure and its inhibitors are now available. Based on the pharmacophore modeling approaches, it is possible to decipher the molecular determinants to inhibit BCR-ABL. We conducted a structure based and ligand based study to identify potent natural compounds as BCR-ABL inhibitor. First kinase inhibitors were docked with the receptor (BCR-ABL) and nilotinib was selected as a pharmacophore due its high binding efficiency. Eleven compounds were selected out of 1457 substances which have mutual pharmacopohre features with nilotinib. These eleven compounds were validated and used for docking study to find the drug like molecules. The best molecules from the final set of screening candidates can be evaluated in cell lines and may represent a novel class of BCR-ABL inhibitors.
Abbreviations:
CML - Chronic myeloid leukemia, PDGFR - Platelet derived growth factor receptor, TKI - Tyrosine kinase inhibitors.
Insights
Researchers identified novel natural compounds as potential inhibitors for BCR-ABL, a key target in chronic myeloid leukemia (CML) treatment. This discovery offers a promising avenue for developing new therapies against imatinib-resistant CML.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Tyrosine kinase inhibitors (TKIs) have transformed cancer treatment, particularly for chronic myeloid leukemia (CML).
- Imatinib resistance is a significant challenge in advanced CML, necessitating the development of alternative therapies.
- Nilotinib, a second-generation TKI, is more potent but also presents side effects.
Purpose of the Study:
- To identify novel natural compounds that can inhibit the BCR-ABL kinase, a driver of CML.
- To explore structure-based and ligand-based approaches for discovering new BCR-ABL inhibitors.
- To find potential drug-like molecules for treating imatinib-resistant CML.
Main Methods:
- Utilized pharmacophore modeling and molecular docking to screen natural compounds against the BCR-ABL kinase.
- Selected nilotinib as a reference pharmacophore due to its high binding efficiency.
- Docked 1457 natural compounds, filtering for those with shared pharmacophore features with nilotinib.
Main Results:
- Identified eleven natural compounds exhibiting pharmacophore similarity to nilotinib.
- Validated these compounds and performed docking studies to assess their potential as BCR-ABL inhibitors.
- Selected promising drug-like molecules from the screened candidates.
Conclusions:
- The identified natural compounds represent a potential novel class of BCR-ABL inhibitors.
- These compounds warrant further evaluation in cell lines for CML treatment.
- This study provides a foundation for developing new therapeutic strategies against resistant CML.
