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

• Published in: Scientific reports Vol. 4; no. 1; p. 6948
• Main Authors: Banavath, Hemanth Naick, Sharma, Om Prakash, Kumar, Muthuvel Suresh, Baskaran, R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.11.2014; Nature Publishing Group
• Subjects: 119/118; 631/114/2163; 631/114/2248; Abl protein; BCR protein; Binding sites; Chemical reactions; Chronic myeloid leukemia; Drug development; Drug Discovery; Drug resistance; Drug Resistance, Neoplasm - genetics; Energy; Free energy; Fusion protein; Fusion Proteins, bcr-abl - chemistry; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Humanities and Social Sciences; Humans; Hydrogen Bonding; Imatinib; Kinases; Leukemia; Life sciences; Ligands; Molecular Conformation; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Mutation; Myeloid leukemia; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteins; Quantitative Structure-Activity Relationship; Science; Side effects; Simulation; Software; Tyrosine kinase inhibitors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep06948

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.