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.