Non-Classical Binding Mechanisms of Ferrocene-Modified Imatinib and Nilotinib Analogues in BCR-ABL1 Kinase Revealed by Computational Analysis.

Rostislava Angelova, Georgi Stavrakov, Danislav S Spassov, Georgi Momekov, Mariyana Atanasova

Journal: Molecules (Basel, Switzerland) 2026;31(12):

PMID: 42357552

Abstract

BACKGROUND

Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity.

METHODS

Ligand geometries were optimized at the B3LYP/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area.

RESULTS

Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation-π contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues.

CONCLUSIONS

Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors.

Address: Chemistry Department, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.; Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.; Chemistry Department, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.; Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 9, 1113 Sofia, Bulgaria.; Centre of Excellence in Informatics and Information and Communication Technologies, Bulgarian Academy of Sciences, Akad. Georgi Bonchev Str., Block 2 and 25A, 1113 Sofia, Bulgaria.; Chemistry Department, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.; Centre of Excellence in Informatics and Information and Communication Technologies, Bulgarian Academy of Sciences, Akad. Georgi Bonchev Str., Block 2 and 25A, 1113 Sofia, Bulgaria.; Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.

DOI: 10.3390/molecules31122156

MeSH Terms: Imatinib Mesylate, Metallocenes, Ferrous Compounds, Fusion Proteins, bcr-abl, Pyrimidines, Molecular Docking Simulation, Protein Kinase Inhibitors, Molecular Dynamics Simulation, Protein Binding, Humans, Binding Sites, Ligands, Tyrosine Kinase Inhibitors