The pharmacological activity of chiral substances in living systems differs since the human body is a highly chiral environment. Enantioselective differences exist in the pharmacokinetics and pharmacodynamics of the various pharmaceutical drugs sold as racemic mixtures. Purification of these racemic mixtures to create enantiopure drugs has become an intense priority for large pharmaceutical companies due to the findings that some enantiomeric forms of certain drugs are harmful to the human body. The design of chromatographic purification systems for the production of single enantiomer drugs is challenging and expensive for pharmaceutical companies. This is owed to the current ‘guess-and-check’ method where method development chemists must screen a large number of combinations of chiral stationary phases, mobile phases, pH, and temperatures to achieve acceptable separation and purification of racemic mixtures. To aid in the currently slow speed of chiral technology advancement, Orochem Technologies along with a molecular simulation team at the Illinois Institute of Technology (IIT) propose development of a predictive molecular model which can guide experimentation and aid its own research scientists as well as those at other drug companies to create solutions to the demanding separation problems. Our first phase of work includes modeling of Orochem’s CSP-1A chiral stationary phase, which we have validated in molecular dynamics simulations. The configurational behavior of the CSP-1A in various solvents in our simulation agrees with experimental observations. We have also developed protocols for generating parameters for both CSPs and chiral molecules utilizing Gaussian and RESP charge fitting. In our study, we have modeled the adsorption of flavanone enantiomers to CSP-1A in various solvent environments and shown agreement with experiments performed on chiral HPLC experiments. We are working to optimize the force field parameters currently to further enhance the effect of various solvents with changing polarity. The successful development of our predictive model will have a substantial impact on the drug development industry. Our proposed molecular model will accelerate drug discovery in pharmaceutical companies and allow for unique drug formulations to be available in the market to consumers that are relying on them for treatment and to extend their lives.
Binwu Zhao attended Zhejiang University in China majored in chemical engineering. He worked on aqueous two-phase polymerization and aerobic oxidative polymerization during in his undergraduate study. He came in 2010 to the US for his senior year through a program between Zhejiang University and North Carolina State University. He then joined Professor Carol K. Hall’s group in December 2010. He has been working on large-scale molecular modeling and multi-scale modeling of ordered/disordered proteins with both conventional molecular dynamics and enhanced sampling methods. He has also been working on the thermodynamic equation of state using statistical associating fluid theory (SAFT). Upon joining Orochem Technologies Inc. at the beginning of September, he has been working on developing a predicative model for chiral molecule separation on various chiral stational phases under different solvent conditions.