This study aimed to perform a rational design for molecularly imprinted polymer (MIP) preparation by using pyrrole as the functional monomer for the detection of renal failure biomarkers. Theoretical optimization and frequency calculations were employed at the M06-2X/6-311++G(d,p) level of theory. As the main results, the proper molar ratio for each monomer–template complex and also the most appropriate solvent and cross-linking agent for each MIP were achieved. In the preparation of the pre-polymerization complex, non-polar solvents were found to perform a better stabilization, mainly those which are not protic solvents. As cross-linking agents, 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 functional monomer. Theoretical infrared (IR) analysis revealed the formation of strong hydrogen bonds between the N–H group of pyrroles and the oxygen atom of template molecules. This result was confirmed by the quantum theory of atoms in molecules. Finally, the proposed theoretical strategy yielded novel, experimentally testable hypotheses for the design of MIPs.

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