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Published on: October 23, 2019
Ponatinib is a pan-BCR-ABL kinase inhibitor: MD simulations and SIE study
Karunakar Tanneeru1, Lalitha Guruprasad
1School of Chemistry, University of Hyderabad, Hyderabad, India.
Abstract:
BCR-ABL kinase domain inhibition can be used to treat chronic myeloid leukemia. The inhibitors such as imatinib, dasatinib and nilotinib are effective drugs but are resistant to some BCR-ABL mutations. The pan-BCR-ABL kinase inhibitor ponatinib exhibits potent activity against native, T315I, and all other clinically relevant mutants, and showed better inhibition than the previously known inhibitors. We have studied the molecular dynamics simulations and calculated solvated interaction energies of native and fourteen mutant BCR-ABL kinases (M244V, G250E, Q252H, Y253F, Y253H, E255K, E255V, T315A, T315I, F317L, F317V, M351T, F359V and H396P) complexed with ponatinib. These studies revealed that the interactions between ponatinib and individual residues in BCR-ABL kinase are also affected due to the remote residue mutations. We report that some residues, Met244, Lys245, Gln252, Gly254, Leu370 and Leu298 do not undergo any conformational changes, while the fluctuations in residues from P-loop, β3-, β5- strands and αC- helix are mainly responsible for ponatinib binding to native and all mutant BCR-ABL kinases. Our work provides the molecular mechanisms of native and mutant BCR-ABL kinases inhibition by ponatinib at atomic level that has not been studied before.
Insights
Ponatinib effectively inhibits BCR-ABL kinase, including resistant mutations common in chronic myeloid leukemia. Molecular dynamics reveal atomic-level interactions explaining its potent binding to native and mutant forms.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Chronic myeloid leukemia (CML) treatment often involves BCR-ABL kinase inhibitors.
- Existing inhibitors like imatinib face resistance due to BCR-ABL mutations.
- Ponatinib is a pan-BCR-ABL kinase inhibitor with activity against resistant mutants, including T315I.
Purpose of the Study:
- To elucidate the molecular mechanisms of ponatinib's inhibition of native and mutant BCR-ABL kinases.
- To investigate the impact of various BCR-ABL mutations on ponatinib binding at an atomic level.
Main Methods:
- Molecular dynamics simulations were performed on native and fourteen mutant BCR-ABL kinases complexed with ponatinib.
- Solvated interaction energies were calculated to assess binding affinities.
- Conformational changes and residue fluctuations were analyzed.
Main Results:
- Ponatinib demonstrates potent activity against native and multiple clinically relevant BCR-ABL mutants.
- Remote residue mutations were found to affect ponatinib-kinase interactions.
- Specific residues (Met244, Lys245, Gln252, Gly254, Leu370, Leu298) showed no conformational changes.
- Fluctuations in P-loop, β3-, β5- strands, and αC- helix residues are crucial for ponatinib binding to both native and mutant kinases.
Conclusions:
- Ponatinib's broad-spectrum inhibition is explained by its interaction with key residues and its ability to accommodate conformational changes induced by mutations.
- This study provides unprecedented atomic-level insights into the molecular basis of ponatinib's efficacy against diverse BCR-ABL kinase variants.
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