An integrated computational and experimental design of amitriptyline-selective molecularly imprinted polymers for electrochemical sensing

Amitriptyline (AMT) is a tricyclic antidepressant with a narrow therapeutic window, necessitating sensitive and selective analytical methods for therapeutic drug monitoring. Molecularly imprinted polymers (MIPs) offer robust molecular recognition yet require rational monomer design to achieve high affinity and selectivity. In this study, a computational–experimental strategy was employed to develop an AMT-selective MIP. Semiempirical PM3 simulations identified methyl methacrylate (MMA) as a suitable functional monomer based on its predicted interaction with AMT. The MIP exhibited higher adsorption capacity than the non-imprinted polymer (NIP), with equilibrium uptake values of 5.76 and 1.36 mg g −1 , respectively. Kinetic analysis reflects contributions from both diffusion-controlled processes and site-specific interactions, while isotherm evaluation showed that the Sips model provided the best fit (R 2 = 0.998). Selective adsorption of AMT over structurally similar nortriptyline (NOR) was observed, with selectivity coefficients of 4.03 (separate batch) and 2.14 (competitive conditions). In addition, strong discrimination against structurally distinct dopamine (DOP) was obtained, with a selectivity coefficient of 20.90, indicating high resistance to non-specific adsorption. When integrated into an electrochemical platform, the MIP-modified electrode enabled AMT detection over the range of 10–500 ng mL −1 with a detection limit of 2.39 ng mL −1 . These results highlight the integration of computational design, adsorption evaluation, and electrochemical response as a rational approach for developing MIP-based systems with selective adsorption and reliable sensing performance.