John Williams
 
Organic and Biological Chemistry
Dr. Williams’ research group is actively involved in the synthesis, analysis, and toxicity screening of arylphosphonium salts. This type of compound readily passes the cell membrane and the mitochondrial membrane. They complex with DNA in vitro and are inhibitors of acetylcholinesterase, both in vitro and in vivo. The literature reports anti-parasitic and anti-cancer activity in vivo for some of these molecules. They are also antibacterials. 
The long-term goal is to prepare novel compounds of this class that will show selective toxicity against bacteria, especially resistant strains, selective inhibition of acetylcholinesterase, which is one approach to treatment of Alzheimer’s Disease, and selective binding of DNA in malignant cells and thereby act as a cancer chemotherapeutic agents.
The current research projects introduce chemistry and biology students to the essentials of drug development research: make the compounds, collect ADMET data, screen the compounds, select the active compounds for in vivo testing.  A parallel project is computational chemistry (see Theoretical Chemistry) of these salts as potential DNA and protein binders.
This work is supported by the  RI College Faculty Research Fund, EPSCoR and RI-INBRE
 
Computational Chemistry
The term in silico has become current in pharmacology research to describe all computational efforts to help select new drug molecules. This involves both the selection of likely compounds for synthesis and the management of large data sets generated by high throughput screening (HTS). Our group does molecular mechanics docking calculations of our molecules and DNA. We calculate QSAR data for all structures with particular attention to the Lipinski Rule of  Five.  There are correlations between these data and the in vitro toxicology data. Modeling structures to better fit the DNA-docking interaction is done computationally to select target molecules for synthesis. We plan to expand this to calculations of protein docking interactions.
This work is supported by the  RI College Faculty Research Fund, EPSCoR and RI-INBRE.
Biochemistry, Organic Chemistry and Toxicology