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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

Backbone RMSD values of drug candidates from both the types (wild and mutant) of protein ligand complexes were generated against the initial structures of protein-ligand complexes during 10,000 ps of molecular dynamics (MD) simulation period.Graphs were plotted using Xmgrace, a 3-D plotting tool.
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f7: Backbone RMSD values of drug candidates from both the types (wild and mutant) of protein ligand complexes were generated against the initial structures of protein-ligand complexes during 10,000 ps of molecular dynamics (MD) simulation period.Graphs were plotted using Xmgrace, a 3-D plotting tool.

Mentions: To ensure the binding stability of the drug candidates in the active site of proteins, ligand positional RMSD of each lead molecule were generated and analyzed as described study41. ST019342 showed more and continues fluctuations in the noticeable window size of 0.2–2.5 nm (Figure 7a) for wild-type and 0.2–4 nm for the mutant BCR-ABL complex (Figure 7b). Co-ordinates of ST019342-BCR-ABL (wild-type and mutant) complex were downloaded from the trajectory in the interval of 1000 ps and investigated in PyMOL for protein-ligand interactions. Our investigation uncovered that ST019342 has an unstable binding affinity towards BCR-ABL. It exhibits weak hydrogen bond interactions with the receptor binding site, which leads to the inefficient inhibition of BCR-ABL. Upon investigation of downloaded timeframe of MD, we observed that after 2 to 5 ns ST019342 was not bound to the binding pocket. It suggests its inability to inhibit the protein target efficiently while other drug candidates have shown stable and strong binding affinity.


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)

Backbone RMSD values of drug candidates from both the types (wild and mutant) of protein ligand complexes were generated against the initial structures of protein-ligand complexes during 10,000 ps of molecular dynamics (MD) simulation period.Graphs were plotted using Xmgrace, a 3-D plotting tool.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Backbone RMSD values of drug candidates from both the types (wild and mutant) of protein ligand complexes were generated against the initial structures of protein-ligand complexes during 10,000 ps of molecular dynamics (MD) simulation period.Graphs were plotted using Xmgrace, a 3-D plotting tool.
Mentions: To ensure the binding stability of the drug candidates in the active site of proteins, ligand positional RMSD of each lead molecule were generated and analyzed as described study41. ST019342 showed more and continues fluctuations in the noticeable window size of 0.2–2.5 nm (Figure 7a) for wild-type and 0.2–4 nm for the mutant BCR-ABL complex (Figure 7b). Co-ordinates of ST019342-BCR-ABL (wild-type and mutant) complex were downloaded from the trajectory in the interval of 1000 ps and investigated in PyMOL for protein-ligand interactions. Our investigation uncovered that ST019342 has an unstable binding affinity towards BCR-ABL. It exhibits weak hydrogen bond interactions with the receptor binding site, which leads to the inefficient inhibition of BCR-ABL. Upon investigation of downloaded timeframe of MD, we observed that after 2 to 5 ns ST019342 was not bound to the binding pocket. It suggests its inability to inhibit the protein target efficiently while other drug candidates have shown stable and strong binding affinity.

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