Identification of novel tyrosine kinase inhibitors for drug resistant T315I mutant BCR-ABL: a virtual screening and molecular dynamics simulations study.
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.
Department of Biochemistry &Molecular biology, School of Life Sciences, Pondicherry University-India.
Hemanth Naick
HN
Banavath
Centre for Bioinformatics, School of Life Sciences, Pondicherry University-India.
Om Prakash
OP
Sharma
Centre for Bioinformatics, School of Life Sciences, Pondicherry University-India.
Muthuvel Suresh
MS
Kumar
Department of Biochemistry &Molecular biology, School of Life Sciences, Pondicherry University-India.
R
R
Baskaran
D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
D008024:Ligands; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl