Chang-Guo Zhan from the University of Kentucky, Lexington, US, introduces the use of computational designs to develop promising therapeutics for treating cocaine addiction and overdoses.

Cocaine addiction and overdoses are major medical and public health problems that continue to defy treatment. The medical and social consequences of cocaine use - such as violent crime, loss in individual productivity, illness, and death - means the development of an effective pharmacological treatment has become a high priority.  Cocaine anti-addiction strategies generally use the classical approach of developing small molecules that interact with one or more neuronal binding sites, with the goal of blocking or counteracting the drug's neuropharmacological actions. Despite decades of effort these approaches have not yet proved successful. 

The inherent difficulties in antagonising a neuronal binding site blocker like cocaine have led to the development of a pharmacokinetic approach that acts directly on the drug to alter its distribution or increase the speed it leaves the body. This could be achieved using a molecule, such as an anti-cocaine antibody, which binds tightly to cocaine preventing it crossing the blood-brain barrier. Alternatively an enzyme that both binds to cocaine and accelerates its metabolism in the body could be used.  These enzymes are designed not to cross the blood-brain barrier, meaning they would have no direct pharmacodynamic action. Ideally this would be a potent enzyme that transforms cocaine into biologically inactive metabolites. 

 

Simulated rate-determining transition state of a high-activity mutant of human butyrylcholinesterase against cocaine

 

A major cocaine-metabolising pathway in primates is hydrolysis catalysed by a plasma enzyme called butyrylcholinesterase (BChE). The metabolites of this pathway are all biologically inactive, meaning that amplifying this pathway could be a good way to speed up cocaine metabolism in users.   However, the catalytic activity of this plasma enzyme is low, taking 45 to 90 minutes for cocaine to be broken down.  This is too long, as it takes only a few minutes for cocaine to travel the central nervous system.  A higher activity BChE that works faster is therefore needed.To achieve this, an enzyme with the desirable catalytic activity needs to be rationally designed.  Rational design is very challenging for this type of system where the chemical reaction step is rate-determining, as traditional computational design based on modeling the enzyme-substrate complex can not be used. Without decreasing the activation free energy for the rate-determining step, an enzymatic reaction cannot go faster, no matter how good the enzyme-substrate binding is. 

To design the perfect enzyme for this purpose, the mechanism the enzyme uses to metabolise cocaine needs to be understood. Once the rate-determining transition state is known, a mutation can be designed with a more stable transition state structure and thus lower activation free energy.

Using state-of-the-art computational studies, encouraging progress has now been made in understanding the cocaine-metabolism mechanism.  The rational design of high-activity mutants of human BChE has also been started using computational designs based on structure and mechanism. In particular, the development of a novel computational design strategy based on transition-state modeling and simulation has led to the discovery of high-activity mutants of human BChE. 

High-activity mutants of enzymes or catalytic antibodies for other therapeutic purposes could also be designed using these rational computer design methods. 

Read Chang-Guo Zhan's perspective on 'Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction' in issue 5, 2008 of Organic and Biomolecular Chemistry.