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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

Total number of inter-molecular H_bond interactions between the drug compounds (DB07107, DB06977, ST013616 and DB04200) and BCR-ABL (mutant and wild).
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f9: Total number of inter-molecular H_bond interactions between the drug compounds (DB07107, DB06977, ST013616 and DB04200) and BCR-ABL (mutant and wild).

Mentions: To determine the stability of hydrogen bonds with the ATP binding site of protein, MD analysis of BCR-ABL and the selected drug candidate's complex stability were monitored during the trajectory period. Hydrogen bond profiles between the selected drugs and BCR-ABL (T315I and wild-type) were calculated using the g_hbond utility of GROMACS. This analysis revealed that DB01172 comprises 6–7 (highest) average H_bonds during the simulation period sharing four H_bonds with Glu282, Lys285, Glu286 and Ile360, and two H_bonds with Asp381 (Figures 9 and 10) in T315I (mutant) while Wild-type showed poor H_bond interactions with 1–2 H_bonds on average during the trajectory period. The same pattern was also observed in the case of ST007180 and ST019342. ST007180 and ST019342 showed less number of hydrogen bond plots in the mutant BCR-ABL compared to wild type. To gain insight into the hydrogen bond instability, we downloaded the drug-receptor complexes in the interval of one ns for DB01172, ST007180 and ST019342. Following which, the structures were superimposed to monitor the binding pose of the drug candidates throughout the trajectories. Our investigation revealed that DB01172 is moving away from the ATP binding site of BCR-ABL in both mutant and wild-type towards the north-west (130°) and east direction (180°) (Figure 11). Compound ST007180 showed satisfactory results, while ST019342 showed slight movement in the binding site.


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)

Total number of inter-molecular H_bond interactions between the drug compounds (DB07107, DB06977, ST013616 and DB04200) and BCR-ABL (mutant and wild).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f9: Total number of inter-molecular H_bond interactions between the drug compounds (DB07107, DB06977, ST013616 and DB04200) and BCR-ABL (mutant and wild).
Mentions: To determine the stability of hydrogen bonds with the ATP binding site of protein, MD analysis of BCR-ABL and the selected drug candidate's complex stability were monitored during the trajectory period. Hydrogen bond profiles between the selected drugs and BCR-ABL (T315I and wild-type) were calculated using the g_hbond utility of GROMACS. This analysis revealed that DB01172 comprises 6–7 (highest) average H_bonds during the simulation period sharing four H_bonds with Glu282, Lys285, Glu286 and Ile360, and two H_bonds with Asp381 (Figures 9 and 10) in T315I (mutant) while Wild-type showed poor H_bond interactions with 1–2 H_bonds on average during the trajectory period. The same pattern was also observed in the case of ST007180 and ST019342. ST007180 and ST019342 showed less number of hydrogen bond plots in the mutant BCR-ABL compared to wild type. To gain insight into the hydrogen bond instability, we downloaded the drug-receptor complexes in the interval of one ns for DB01172, ST007180 and ST019342. Following which, the structures were superimposed to monitor the binding pose of the drug candidates throughout the trajectories. Our investigation revealed that DB01172 is moving away from the ATP binding site of BCR-ABL in both mutant and wild-type towards the north-west (130°) and east direction (180°) (Figure 11). Compound ST007180 showed satisfactory results, while ST019342 showed slight movement in the binding site.

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