# Green Strategies for Molecularly Imprinted Polymer Development
## Green Strategies in MIP Development
### Computational Tools on Rational Design of MIPs  
Computational tools have been increasingly used to replace combinatorial screening or trial-and-error methods to produce MIPs. Combinatorial synthesis and screening were the most used strategies for rational design of molecularly imprinted polymers [137]. However, combinatorial synthesis has some drawbacks. For example, to study two different parameters using 100 monomers, it would be necessary to prepare more than one thousand polymers. Molecular modeling and thermodynamic calculations are a potential solution for this problem [138]. Molecular mechanics (MM) provides a qualitative description of the system based on potential energy, and allows the calculations to be run in an easy way. Atoms are considered as balls which have a specific radius and a string. The atom sizes, bond geometry, and strength are determined using empirical data from X-ray crystallography and NMR experiments [139]. AMBER, HyperChem 501, GROMACS, Gaussian [139], MOE, RasMol, QMol, Raster 3D, and AGM Build are some of most used MM software packages used in several applications. The main limitation of computational design of MIPs is based on thermodynamic calculations [140] for multicomponent systems. However molecular modelling of complex systems, including interactions of polymers with template, solvent, and other molecules are difficult, due to the requirements of computational workstation [139]. Some drawbacks are associated with these programs, since some of them cannot generate a clear result. In the end, the results have to be crossed, requiring a lot of time to organize data and make conclusions. The [PERSON] group developed a methodology that can greatly simplify this process, because instead of modelling the polymer, they focus on the monomer mixture and the interactions between monomers, template, and solvent, using the program SYBYLTM, significantly reducing the computational load [6; 9; 11]. SYBYLTM is a user-friendly program typically applied in drug design [141]. The [PERSON] group successfully adapted this program to measure affinities between molecules involved in the MIP synthesis, performing rational MIP design [139]. In 2001, [PERSON] et al. [140; 142] reported for the first time the computational design of a MIP specific to ephedrine using SYBYLTM, where a virtual library containing all functional monomers was previously created and further screened using the LEAPFROGTM algorithm against the template. The monomers which gave the highest binding scores, ITA, MAA, HEMA, AA, and 2-Vpy were selected to be experimentally used in the co-polymerization with EGDMA (crosslinker), chloroform, and THF as porogenic solvents, and 1,1\({}^{\prime}\)-azobis(cyclohexanecarbonitrile) as initiator, overnight at 80 \({}^{\circ}\)C. Copolymers were obtained as bulk material which were ground using a SL2 suspension grinder and wet-sieved to collect a final fraction of the polymer with particle size between 38 and 106 \(\upmu\)m. The five MIPs were packed into HPLC columns, and their performances were evaluated. ITA and MAA-based MIPs showed strong interactions with ephedrine. As a result, a clear correlation was attained between the modelling results and the performance of the materials, meaning that the computational studies provided a useful tool to predict the affinity and specificity of the MIP mimicking real experiments. In 2002, [PERSON] et al. [143] explored the use of a SYBYL-computational approach for rational design of MIPs towards cyanobacterial toxin mycrocystin-LR. The molecular modelling software uses a virtual library containing all polymerizable monomers that are screened against the target molecule. The best suitable monomer was the one which generated higher monomer-template binding energies. 2-Methyl-1-propanesulfonic acid (AMPSA) was selected as the best monomer, followed by imidazole-4-acrylic acid ethyl ester (UAEE), and MAA.