In this research, a rational design based on density functional theory (DFT) was performed for molecularly imprinted polymer (MIP) biosensors using pyrrole and acrylamide as the functional monomers for selective detection of renal failure biomarkers, i.e. urea, creatinine, uric acid and xanthine. Theoretical optimization and frequency calculations were employed at M06-2X/6–311 +  + G(d,p) level of theory. As the main results, the proper molar ratio for each monomer–template complex, and the most appropriate solvent and cross-linking agent for MIP preparation were achieved. In the preparation of the pre-polymerization complexes, non-polar aprotic solvents were found to perform better stabilization. As cross-linking agent, better results were obtained for divinylbenzene. The selectivity tests showed a high affinity of the studied MIPs for each template compared to its structural analogs. The frontier molecular orbital (FMO) distribution, molecular electrostatic potentials (MEPs), and natural bond orbital (NBO) analysis were explored to predict the potential active sites in the templates and monomers. Theoretical infrared (IR) analysis revealed the formation of strong hydrogen bonds between the template and monomer molecules. This result was confirmed by the quantum theory of atoms in molecules. Finally, this study constitutes a useful protocol to predict optimal conditions, which can considerably reduce the time and cost of MIPs preparation.

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