Summer Research with NIDA 2013: Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment

Development of a truly effective anti-cocaine medication has been very challenging, particularly for treatment of cocaine overdose. There is still no FDA-approved anti-cocaine medication. Enhancing cocaine metabolism by administration of butyrylcholinesterase (BChE) has been recognized as a promising treatment strategy for cocaine abuse. However, the catalytic activity of this plasma enzyme is low against the naturally occurring (-)-cocaine. Our recent integrated computational-experimental effort has led to discovery of highactivity mutants of human BChE, known as cocaine hydrolases (CocHs), with >1,000-fold improved catalytic efficiency against cocaine compared to wild-type BChE. In vivo evidences indicate that our discovered CocHs are promising candidates for development of an anti-cocaine medication, especially for the overdose treatment. The high school student (Max) will first be instructed to study how BChE and CocHs interact with cocaine, norcocaine, cocaethylene, and other drugs/potential inhibitors by using state-of-the-art techniques of computational chemistry. The modeling studies will be followed by in vitro experimental tests to characterize BChE and CocHs for their interactions with these ligands. The detailed understanding of the protein-ligand interactions will enhance our knowledge base for rational design of a better therapeutic enzyme for treatment of cocaine overdose and addiction. RELEVANCE