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Updated: May 5, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Identification of new dasatinib analogues targeting mutated BCR-ABL1: virtual screening, molecular docking, and
Mohammad Jahoor Alam1, Arshad Jamal2, Shaik Daria Hussain3
1Department of Biology, College of Science, University of Hail, Ha'il, Saudi Arabia. j.alam@uoh.edu.sa.
Abstract:
Drug resistance is a major challenge in cancer chemotherapy and accounts for a majority of cancer-related deaths globally. One of the well-identified and characterised mechanisms of drug resistance in chronic myeloid leukaemia (CML) is the presence of BCR-ABL1 mutations, which is responsible for resistance against first-line tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib. In the present work, we first performed a three-tier virtual screening against the human tyrosine kinase ABL1 protein (PDB ID: 2GQG). Top-performing compounds were then selected for molecular dynamics (MD) simulation studies at 500 ns to understand their affinity, dynamics, and stability with the target protein. Finally, density functional theory (DFT) studies at the B3LYP/6-31G* level of theory were conducted to elucidate the molecular features of the identified compounds. Based on the docking scores (-14.80 to -13.79 kcal/mol) and ADMET profiles, we identify 45375848, 88575518, and 23589024 as the most promising candidates. All three compounds contained N-(2-chloro-6-methylphenyl)-2-(methylamino) thiazole-5 carboxamide as the common fragment. MD parameters (RMSD, RMSF and SSE) further complemented the docking results, showing stabilisation of the ABL1 protein in the presence of identified compounds. High drug-likeness, acceptable pharmacokinetic profile and other molecular features warrant the drug-like behaviour of the compounds. Overall, this study highlights promising ABL1 inhibitors, laying the ground for further investigations.
Insights
New drug candidates show promise in overcoming cancer drug resistance. Computational studies identified three compounds that stabilize the ABL1 protein, potentially inhibiting chronic myeloid leukemia progression.
Area of Science:
- Computational chemistry and drug discovery
- Molecular modeling and simulation
- Oncology and cancer therapeutics
Background:
- Drug resistance, particularly BCR-ABL1 mutations, is a significant cause of cancer chemotherapy failure and mortality.
- First-line tyrosine kinase inhibitors (TKIs) are often ineffective against resistant chronic myeloid leukemia (CML) strains.
Purpose of the Study:
- To identify novel drug candidates targeting the ABL1 protein to overcome TKI resistance in CML.
- To computationally screen and evaluate potential inhibitors for their binding affinity, stability, and drug-like properties.
Main Methods:
- Multi-tiered virtual screening of compounds against the ABL1 protein (PDB ID: 2GQG).
- Molecular dynamics (MD) simulations (500 ns) to assess compound-protein interactions and stability.
- Density functional theory (DFT) calculations (B3LYP/6-31G*) to analyze molecular characteristics.
Main Results:
- Identified three lead compounds (45375848, 88575518, 23589024) with high docking scores (-14.80 to -13.79 kcal/mol) and favorable ADMET profiles.
- All identified compounds share a common N-(2-chloro-6-methylphenyl)-2-(methylamino)thiazole-5-carboxamide fragment.
- MD simulations confirmed stabilization of the ABL1 protein by the candidate compounds, supported by RMSD, RMSF, and SSE analyses.
Conclusions:
- The identified compounds exhibit high drug-likeness and promising pharmacokinetic profiles, indicating potential as effective ABL1 inhibitors.
- These findings provide a strong foundation for further experimental investigation into novel CML therapies.
- The study highlights the utility of integrated computational approaches in discovering new anti-cancer drug candidates.
