Unraveling the molecular recognition mechanism of voriconazole and functional monomers in molecularly imprinted polymer design

• B3LYP def2TZVP with DFT-D4 dispersion was used to examine the host-guest interaction of the voriconazole molecularly imprinted polymer. • HEMA was the optimal monomer in complex formation in chloroform, ESP, QTAIM, NCI-RDG, IRI, and IGM analyses revealed the key non-covalent interactions responsible for the MIP’s recognition specificity. • Laboratory investigation using the association constant and Job plot analysis verified the computational study. Molecularly imprinted polymers (MIP) offer highly selective recognition toward target analytes, yet their performance critically depends on the strength and nature of template–monomer interactions in the pre-polymerization stage. This study aims to develop a novel, integrative host-guest interaction approach that combines theoretical and experimental methodologies to support a rational MIP design framework. The computational elucidates the molecular recognition mechanism between voriconazole and monomers relevant to MIP formation, providing a detailed description of the complex stability and selectivity governed by non-covalent interactions. The interaction between voriconazole and 2-hydroxyethyl methacrylate (HEMA) was stabilized predominantly by hydrogen bonding and van der Waals interactions using a combination of energy analysis and electron density descriptors, supported by favorable binding energy and orbital overlap characteristics. Further investigation of multi-monomer complexes revealed that a 1:7 template-to-monomer ratio yields the most stable configuration, indicating cooperative binding effects. Non-covalent interaction analyses provided a comprehensive visualization of the domains of interaction and electron density features responsible for imprint specificity. Laboratory investigation, including the association constant and Job plot methods, confirmed the interaction of voriconazole and HEMA complex with a Ka value of 660±3729 M−1 and 1:7 template-to-monomer ratio at equilibrium in chloroform. These findings enhance the understanding of how non-covalent interactions govern the establishment of high-fidelity recognition sites and demonstrate the potential of computational assessments for the rational design of MIP, with implications for subsequent laboratory synthesis of MIP-based sensors.