Scientists have finally calculated how to inhibit an enzyme linked to anxiety. Quantum and molecular mechanics are proving useful tools for drug design where other approaches fail, says the international team behind the research.

The quantum mechanics/molecular mechanics (QM/MM) approach has allowed Adrian Mulholland at the University of Bristol, UK, and colleagues in Italy and the US, to identify the correct binding orientation for an inhibitor of enzyme fatty acid amide hydrolase (FAAH). Knowledge of the mechanism will help the design of more potent inhibitors, say the researchers.

FAAH is a promising drug target for the treatment of anxiety, pain and depression and its inhibitors have shown analgesic and anti-depressant effects in rats. Carbamate inhibitors are known to bind to FAAH, resulting in covalent modification of catalytic residues and a corresponding loss of enzyme function, although the exact reaction mechanism has been unclear until now. Previously, conventional computational experiments revealed two possible binding orientations for FAAH inhibitors, but were unable to determine which of these leads to enzyme inhibition.

Using the QM/MM approach to model the inhibitor binding process for both orientations, Mulholland and his colleagues have finally solved the mystery. The QM/MM approach finds the intermediates and transition states on the reaction profiles for each binding orientation; the orientation that leads to inhibition has the lowest energy reaction pathway. 'The barrier for reaction was very high for one orientation,' said Mulholland. 'Only one orientation could feasibly produce the experimentally observed product.'

Hua Guo, an expert in modelling enzyme catalysis at the University of New Mexico, in Albuquerque, US, welcomed the research. 'This work showcases the power of the computational approach to understand enzyme binding and catalysis and underscores the importance of substrate binding orientation in enzyme catalysis,' said Guo.

Russell Johnson