Limits...
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.

Show MeSH

Related in: MedlinePlus

2-D Structures of the finally selected seven lead molecules have been shown in the figure.(1) DB07107, (2) DB06977, (3) ST013616, (4) DB04200, (5) ST007180, (6) ST019342, and (7) DB01172.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4225644&req=5

f1: 2-D Structures of the finally selected seven lead molecules have been shown in the figure.(1) DB07107, (2) DB06977, (3) ST013616, (4) DB04200, (5) ST007180, (6) ST019342, and (7) DB01172.

Mentions: Results of binding pose analysis of seven lead molecules with better binding affinity and higher binding free energy than the reference compounds. Four of which, designated DB07107, DB06977, DB04200 and DB0117, were from DrugBank and ST007180, ST013616 and ST019342 were from the ligand.info database. The 2D conformations and drug details are given in (Figure 1).


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)

2-D Structures of the finally selected seven lead molecules have been shown in the figure.(1) DB07107, (2) DB06977, (3) ST013616, (4) DB04200, (5) ST007180, (6) ST019342, and (7) DB01172.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: 2-D Structures of the finally selected seven lead molecules have been shown in the figure.(1) DB07107, (2) DB06977, (3) ST013616, (4) DB04200, (5) ST007180, (6) ST019342, and (7) DB01172.
Mentions: Results of binding pose analysis of seven lead molecules with better binding affinity and higher binding free energy than the reference compounds. Four of which, designated DB07107, DB06977, DB04200 and DB0117, were from DrugBank and ST007180, ST013616 and ST019342 were from the ligand.info database. The 2D conformations and drug details are given in (Figure 1).

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