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<p>The molecular recognition complex of the oral multi-kinase inhibitor namely: Regorafenib, and β-cyclodextrin can enhance the solubility of this drug and reduce the side effects. In this work, we elucidate the nature of interactions and the driving forces that conduct the Regorafenib and β-cyclodextrin complexation, employing manual and automatic molecular docking methods, using B97-3c\def2-mTZVP method. These two docking methods are widely used in many works, but some researchers focus on one method rather than another, which could indicate the preference of one of them over the other. In the context of Regorafenib and β-cyclodextrin complexation study the evaluation of the outcomes of the manual and automatic molecular docking methods are achieved. The optimization and energetic study favored two complex structures with similar guest molecule orientations namely model B (from manual method) and model C (from automatic method). Thus, the Regorafenib is partially embedded in the β-cyclodextrin cavity, and the picolinamide ring is located inside the β-cyclodextrin where the trifluoromethyl phenyl ring is located outside. Moreover, the global reactivity indices indicate the stability of the favored complexes in the water phase. Further, the TD-DFT reveals different electronic transitions between the host and the guest which indicate the direction of the charge flow from β-cyclodextrin to Regorafenib. The NMR-GIAO data demonstrate the occurrence of complexation and the predictive performance of two conformational research approaches. Finally, the Quantum Theory Atom in Molecule (QTAIM), Non-Covalent Interaction analysis (NCI-RDG) and Energy Decomposition Analysis (EDA-FF) were used to identify the different interactions that occur during the inclusion process. Despite the similar orientation of the guest molecule in models B and C, the atom coordinates of the guest in each model make sense when a detailed analysis of absorption transitions, NMR, and non-covalent interactions is taken into account. These results establish general trends in the performance of the conformational research approaches.</p>

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Regorafenib and β-cyclodextrin complex: theoretical investigation using manual and automatic molecular docking approaches

  • 期刊论文

  • 发表日期：

    2026年6月29日

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  • Houdhaifa R. Belhouchet,
  • Tahar Abbaz,
  • Nikola Stamenković,
  • Didier Villemin

摘要

The molecular recognition complex of the oral multi-kinase inhibitor namely: Regorafenib, and β-cyclodextrin can enhance the solubility of this drug and reduce the side effects. In this work, we elucidate the nature of interactions and the driving forces that conduct the Regorafenib and β-cyclodextrin complexation, employing manual and automatic molecular docking methods, using B97-3c\def2-mTZVP method. These two docking methods are widely used in many works, but some researchers focus on one method rather than another, which could indicate the preference of one of them over the other. In the context of Regorafenib and β-cyclodextrin complexation study the evaluation of the outcomes of the manual and automatic molecular docking methods are achieved. The optimization and energetic study favored two complex structures with similar guest molecule orientations namely model B (from manual method) and model C (from automatic method). Thus, the Regorafenib is partially embedded in the β-cyclodextrin cavity, and the picolinamide ring is located inside the β-cyclodextrin where the trifluoromethyl phenyl ring is located outside. Moreover, the global reactivity indices indicate the stability of the favored complexes in the water phase. Further, the TD-DFT reveals different electronic transitions between the host and the guest which indicate the direction of the charge flow from β-cyclodextrin to Regorafenib. The NMR-GIAO data demonstrate the occurrence of complexation and the predictive performance of two conformational research approaches. Finally, the Quantum Theory Atom in Molecule (QTAIM), Non-Covalent Interaction analysis (NCI-RDG) and Energy Decomposition Analysis (EDA-FF) were used to identify the different interactions that occur during the inclusion process. Despite the similar orientation of the guest molecule in models B and C, the atom coordinates of the guest in each model make sense when a detailed analysis of absorption transitions, NMR, and non-covalent interactions is taken into account. These results establish general trends in the performance of the conformational research approaches.