# Green Strategies for Molecularly Imprinted Polymer Development
## Green Strategies in MIP Development
### Computational Tools on Rational Design of MIPs
[149] reported an atomistic model to design monomers and polymers for molecular imprinting of THO and its derivatives using molecular dynamics (MD) simulations to predict the binding energies. This approach was applied in five template molecules, THO, and its derivatives (theobromine, theophylline-8-butanoic acid, caffeine, and theophylline-7-acetic acid) and in the end, minimized structures were attained and stable complexes were obtained using MM. These authors also reported an extension of the previous work, where in this case, the solvent, ethanol, was added to molecular simulations [150]. They showed that electrostatic interactions had a strong impact on the formation of the molecular imprinting structures. Moreover, the simulated results showed that monomers or polymers interacted with template preferentially by -COOH or CH\({}_{2}\)=CH-. Additionally, it was verified that a template without functional side groups are suitable for molecular imprinting technology. Furthermore, the presence of solvent favored the stability of THO-monomer/polymer complex over its derivatives. SYBYL computationally-designed MIPs towards to herbicide simazine for environmentally control of algae was also reported in 2005 by [PERSON] et al. [151]. [PERSON] et al. [152] reported a GAUSSIAN computational approach for the rational design of homovanillic acid (HVA)-MIPs. Density functional theory (DFT) methodology was used to design MIPs, allowing the choice the most suitable monomer and solvent to prepare MIPs. A comparison between stabilization energies of the pre-polymerization adducts between template and functional monomer is the basis of this methodology. The same group [153] also provided an alternative approach, DFT-computational prediction and experimental evaluation for HVA-MIP, in which trifluoromethacrylic acid (TFMAA)/toluene was the best combination of functional monomer/solvent that promoted the most stable pre-polymerization adducts. [PERSON] et al. [154] proposed a combination of MD, MM, docking and site mapping computational methods to design highly selective THO-MIP in ACN. MAA and MMA were used as monomers to simulate the final polymer. This methodology was able to predict the affinity and selectivity of MAA-MIP towards THO and analogue molecules (caffeine, theobromine, xanthine, and 3-methylxanthine). [PERSON] et al. [155] reported a DFT-molecular simulation and experimental validation of the influence of solvent on adsorption capacity of THO-MIPs. Computational simulations indicated chloroform as the most suitable solvent to prepare THO-MIP compared to THF and DMSO. [PERSON] et al. [156] described MMFF94 force field as a computational tool to evaluate the properties of paracetamol-MIPs. The binding energies between template and monomers can be calculated through this model, as well as the most possible conformations of template-monomer when they are interacting. [PERSON] et al. [157] proposed a quantitative structure-imprinting factor computational approach with application on MIP design, which correlates the template-monomer complex with the IF. The QSPR evaluation correlates the monomer-template structure with the IF based on quantum chemical descriptors derived from single point calculation at B3 LYP/6-31G(d) of geometrically optimized structure at the HF/3-21G(d) level of theory. The analysis of MIP particles from the literature was used to compute the imprinting factor using molecular descriptors derived from charge density-based electronic properties of molecules in which reliable results were predicted with high correlation coefficients. In addition, the mobile phase, which can be aqueous, pH, dielectric constant of binary solvents, and ionic strength of aqueous buffers was shown to have a strong impact on the performance of the predictive QSPR model. This feasible methodology could serve as a basis for the development of software packages which are able to predict MIP performance before testing. [PERSON] et al.