Applications of quantum mechanics and molecular mechanics in understanding of organic reaction mechanisms and ligand-protein interactions

Understanding of chemical interactions between molecules is critically important in obtaining a global picture of an organism functioning.I used highly accurate quantum mechanical methods to study reaction pathways and conformational preferences in a model Chichibabin reaction. This classical reaction has been influential not only in the development of heterocyclic chemistry but also in production of aminopyridines and their derivatives for the pharmaceutical industry. The mechanism proposed on the calculations is consistent with earlier experimental observations such as obtaining a byproduct and hydrogen gas formation.As an extension of the use of the computational methods, I used molecular mechanics methods to obtain different models of interactions between proteins and small molecules. This technique is widely used in zero-stage drug development to identify potent ligands for a particular protein. In the first application we found five potential inhibitor lead compounds for enzyme fructose-1,6-biphosphatase participating in regulation of blood glucose level. We also applied this technique to find potent inhibitors of acetylcholinesterase. Application of these compounds carries the promise of becoming potential therapeutics against type II diabetes (FBPase) and Alzheimer's disease (AChE) respectively and their use may be extended to other similar types of diseases.In further studies, I studied proteins and their ability to bind specific small molecules. An interesting example is the xenobiotic and steroid-responsive human pregnane X-receptor (PXR). The reason it binds a broad range of structurally diverse compounds is the unique smooth and almost spherical binding site with five hot spots located on four different sites of the pocket and one close to the center. Depending on the ligand shape and size, it fits into two, three or more hot spot regions. The importance of PXR is associated with the identification of the presence of steroids and xenobiotic, and with responses up-regulates the expression of proteins involved in detoxification in the body. Study was extended to the peroxisome proliferator-activated receptor (PPAR) gamma that binds phthalates, the class of organic compounds widely used as plasticizers in chemical industry.