Bioengineering Insights into Orientation and Structural Stability of Phenyl Methyl Thiazole Derivative with β-Cyclodextrin Through Computational Modeling

This study explores the formation of inclusion complexes between a newly synthesized N-(2-(butylamino)-2-oxoethyl)-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxamide with β-cyclodextrin using density functional theory with dispersion correction (DFT-D3) at the B3LYP-GD3/3-21G, 6-31G(d), 6-31G’(d), and 6-311G(d) levels. Two orientations are considered: in Orientation A, the 3-cyano-4-isobutoxyphenyl moiety interacts with the primary hydroxyl rim of β-cyclodextrin, while in Orientation B, the amide side chain faces the wider rim. Complexation energies and thermodynamic parameters are calculated to determine stability. Electronic properties, including HOMO-LUMO energies, and global reactivity descriptors, such as electronegativity (χ), chemical potential (μ), hardness (η), and electrophilicity index (ω), are evaluated. Non-covalent interaction (NCI) analysis is also performed to visualize interaction sites. The results reveal the significant influence of orientation on the host–guest complex stability and electronic properties, providing valuable insights into cyclodextrin-based encapsulation systems. The study provides a computational blueprint for engineering cyclodextrin-based bio-functional systems, where orientation-controlled inclusion governs stability, reactivity, and performance. This can significantly impact the development of smart drug delivery systems, biosensors, and multifunctional biomaterials in modern bioengineering.