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Identification of novel tyrosine kinase inhibitors for drug resistant T315I mutant BCR-ABL: a virtual screening and molecular dynamics simulations study.

Banavath HN, Sharma OP, Kumar MS, Baskaran R - Sci Rep (2014)

Bottom Line: Currently available drugs in the market are effective against CML; however, side-effects and drug-resistant mutations in BCR-ABL limit their full potential.The selected compounds showed least ΔG score -71.53 KJ/mol to maximum -126.71 KJ/mol in both wild type and drug resistant T315I mutant BCR-ABL.Results uncovered seven lead molecules, designated with Drug-Bank and PubChem ids as DB07107, DB06977, ST013616, DB04200, ST007180 ST019342, and DB01172, which shows docking scores higher than imatinib and ponatinib.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry &Molecular biology, School of Life Sciences, Pondicherry University-India.

ABSTRACT
BCR-ABL tyrosine kinase plays a major role in the pathogenesis of chronic myeloid leukemia (CML) and is a proven target for drug development. Currently available drugs in the market are effective against CML; however, side-effects and drug-resistant mutations in BCR-ABL limit their full potential. Using high throughput virtual screening approach, we have screened several small molecule databases and docked against wild-type and drug resistant T315I mutant BCR-ABL. Drugs that are currently available, such as imatinib and ponatinib, were also docked against BCR-ABL protein to set a cutoff value for our screening. Selected lead compounds were further evaluated for chemical reactivity employing density functional theory approach, all selected ligands shows HLG value > 0.09900 and the binding free energy between protein-ligand complex interactions obtained was rescored using MM-GBSA. The selected compounds showed least ΔG score -71.53 KJ/mol to maximum -126.71 KJ/mol in both wild type and drug resistant T315I mutant BCR-ABL. Following which, the stability of the docking complexes were evaluated by molecular dynamics simulation (MD) using GROMACS4.5.5. Results uncovered seven lead molecules, designated with Drug-Bank and PubChem ids as DB07107, DB06977, ST013616, DB04200, ST007180 ST019342, and DB01172, which shows docking scores higher than imatinib and ponatinib.

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Related in: MedlinePlus

Time dependence of root mean square deviations (RMSDs) of the Backbone of mutant (T3I51)and wild type of BCR-ABL have been shown in figure against the initial structure during 10,000 ps molecular dynamics (MD) simulation.
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f6: Time dependence of root mean square deviations (RMSDs) of the Backbone of mutant (T3I51)and wild type of BCR-ABL have been shown in figure against the initial structure during 10,000 ps molecular dynamics (MD) simulation.

Mentions: To compare the structural behavior and flexibility of the wild-type and mutant BCR-ABL, all lead compounds were incorporated in Gromacs4.5.5 and MD was performed for 10 ns of each complexes. Root mean square deviations (RMSD) of the wild-type and mutant BCR-ABL were calculated against their initial structure in the protein-ligand complexes and graphs were generated to compare the flexibility of the backbone of the proteins using the Xmgrace software. Throughout the simulation period, no significant fluctuations were observed in the backbone of the wild-type and mutant T315I BCR-ABL, implying that the binding of drug candidates at the active site of the proteins is not only stable and strong but also does not disturb the protein backbone stability (Figure 6).


Identification of novel tyrosine kinase inhibitors for drug resistant T315I mutant BCR-ABL: a virtual screening and molecular dynamics simulations study.

Banavath HN, Sharma OP, Kumar MS, Baskaran R - Sci Rep (2014)

Time dependence of root mean square deviations (RMSDs) of the Backbone of mutant (T3I51)and wild type of BCR-ABL have been shown in figure against the initial structure during 10,000 ps molecular dynamics (MD) simulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4225644&req=5

f6: Time dependence of root mean square deviations (RMSDs) of the Backbone of mutant (T3I51)and wild type of BCR-ABL have been shown in figure against the initial structure during 10,000 ps molecular dynamics (MD) simulation.
Mentions: To compare the structural behavior and flexibility of the wild-type and mutant BCR-ABL, all lead compounds were incorporated in Gromacs4.5.5 and MD was performed for 10 ns of each complexes. Root mean square deviations (RMSD) of the wild-type and mutant BCR-ABL were calculated against their initial structure in the protein-ligand complexes and graphs were generated to compare the flexibility of the backbone of the proteins using the Xmgrace software. Throughout the simulation period, no significant fluctuations were observed in the backbone of the wild-type and mutant T315I BCR-ABL, implying that the binding of drug candidates at the active site of the proteins is not only stable and strong but also does not disturb the protein backbone stability (Figure 6).

Bottom Line: Currently available drugs in the market are effective against CML; however, side-effects and drug-resistant mutations in BCR-ABL limit their full potential.The selected compounds showed least ΔG score -71.53 KJ/mol to maximum -126.71 KJ/mol in both wild type and drug resistant T315I mutant BCR-ABL.Results uncovered seven lead molecules, designated with Drug-Bank and PubChem ids as DB07107, DB06977, ST013616, DB04200, ST007180 ST019342, and DB01172, which shows docking scores higher than imatinib and ponatinib.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry &Molecular biology, School of Life Sciences, Pondicherry University-India.

ABSTRACT
BCR-ABL tyrosine kinase plays a major role in the pathogenesis of chronic myeloid leukemia (CML) and is a proven target for drug development. Currently available drugs in the market are effective against CML; however, side-effects and drug-resistant mutations in BCR-ABL limit their full potential. Using high throughput virtual screening approach, we have screened several small molecule databases and docked against wild-type and drug resistant T315I mutant BCR-ABL. Drugs that are currently available, such as imatinib and ponatinib, were also docked against BCR-ABL protein to set a cutoff value for our screening. Selected lead compounds were further evaluated for chemical reactivity employing density functional theory approach, all selected ligands shows HLG value > 0.09900 and the binding free energy between protein-ligand complex interactions obtained was rescored using MM-GBSA. The selected compounds showed least ΔG score -71.53 KJ/mol to maximum -126.71 KJ/mol in both wild type and drug resistant T315I mutant BCR-ABL. Following which, the stability of the docking complexes were evaluated by molecular dynamics simulation (MD) using GROMACS4.5.5. Results uncovered seven lead molecules, designated with Drug-Bank and PubChem ids as DB07107, DB06977, ST013616, DB04200, ST007180 ST019342, and DB01172, which shows docking scores higher than imatinib and ponatinib.

Show MeSH
Related in: MedlinePlus