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<p>The BCR-ABL tyrosine kinase remains one of the most important targets in the treatment of chronic myeloid leukemia (CML), and targeting the inactive DFG-out conformation is a key approach to selective type-II inhibition of BCR-ABL. In the present work, a structure-based integrated computational workflow was carried out to design and evaluate potential new BCR-ABL type-II inhibitors in their inactive kinase conformation. The conserved BCR-ABL pharmacophoric framework of clinically approved inhibitors was used to create a virtual library of 942 derivatives by scaffold optimization and systematic enumeration of R-groups. Redocking experiments were used to validate the docking protocol and resulted in an RMSD of ~ 1.7 Å. It was then validated using receiver operating characteristic (ROC) analysis with 10 known BCR-ABL inhibitors and 88 decoys from DUD-E, yielding an area under the curve (AUC) of 0.910, indicating a reliable and predictive docking workflow. The compounds generated were initially screened by high-throughput virtual screening (HTVS) and then prioritized by predicting gastrointestinal absorption and drug-likeness (ADMET). The top 50 derivatives were then optimized using extra-precision (XP) molecular docking and post-docking MM-GBSA. Seven top-ranked compounds exhibited highly favorable binding affinities in the inactive DFG-out conformation, with XP docking scores ranging from − 15.149 to -13.182&#xa0;kcal/mol, compared with − 13.941&#xa0;kcal/mol for imatinib. Of these, compound C48 showed the highest docking score (-15.149&#xa0;kcal/mol), had stable hydrogen-bonding interactions with MET318, THR315, and ASP381, and was also extensively hydrophobic in the allosteric pocket involved in type-II inhibition. Comparative docking analysis with the active DFG-in conformation revealed a significant conformational preference for the inactive kinase state, thereby confirming their selective type-II inhibitory activities. The stability of the selected complexes during 100 ns molecular dynamics simulations was also confirmed, and trajectory-based MM-GBSA analysis showed the average binding free energies of C48 (-99.97&#xa0;kcal/mol) and C208 (-97.12&#xa0;kcal/mol) were much more favorable than that of imatinib (-94.87&#xa0;kcal/mol). Additionally, the frontier molecular orbital distributions were confirmed by DFT calculations, indicating suitability for stable intermolecular interactions. Overall, the results presented show that C48 is an attractive scaffold for the future development of selective BCR-ABL type-II inhibitors targeting the inactive DFG-out conformation.</p>

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Structure-based virtual screening and lead identification of novel protein kinase inhibitors through integrated computational approaches

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Mohammed Abdulaali Sahib

摘要

The BCR-ABL tyrosine kinase remains one of the most important targets in the treatment of chronic myeloid leukemia (CML), and targeting the inactive DFG-out conformation is a key approach to selective type-II inhibition of BCR-ABL. In the present work, a structure-based integrated computational workflow was carried out to design and evaluate potential new BCR-ABL type-II inhibitors in their inactive kinase conformation. The conserved BCR-ABL pharmacophoric framework of clinically approved inhibitors was used to create a virtual library of 942 derivatives by scaffold optimization and systematic enumeration of R-groups. Redocking experiments were used to validate the docking protocol and resulted in an RMSD of ~ 1.7 Å. It was then validated using receiver operating characteristic (ROC) analysis with 10 known BCR-ABL inhibitors and 88 decoys from DUD-E, yielding an area under the curve (AUC) of 0.910, indicating a reliable and predictive docking workflow. The compounds generated were initially screened by high-throughput virtual screening (HTVS) and then prioritized by predicting gastrointestinal absorption and drug-likeness (ADMET). The top 50 derivatives were then optimized using extra-precision (XP) molecular docking and post-docking MM-GBSA. Seven top-ranked compounds exhibited highly favorable binding affinities in the inactive DFG-out conformation, with XP docking scores ranging from − 15.149 to -13.182 kcal/mol, compared with − 13.941 kcal/mol for imatinib. Of these, compound C48 showed the highest docking score (-15.149 kcal/mol), had stable hydrogen-bonding interactions with MET318, THR315, and ASP381, and was also extensively hydrophobic in the allosteric pocket involved in type-II inhibition. Comparative docking analysis with the active DFG-in conformation revealed a significant conformational preference for the inactive kinase state, thereby confirming their selective type-II inhibitory activities. The stability of the selected complexes during 100 ns molecular dynamics simulations was also confirmed, and trajectory-based MM-GBSA analysis showed the average binding free energies of C48 (-99.97 kcal/mol) and C208 (-97.12 kcal/mol) were much more favorable than that of imatinib (-94.87 kcal/mol). Additionally, the frontier molecular orbital distributions were confirmed by DFT calculations, indicating suitability for stable intermolecular interactions. Overall, the results presented show that C48 is an attractive scaffold for the future development of selective BCR-ABL type-II inhibitors targeting the inactive DFG-out conformation.