Modeling biotransformation reactions by combined quantum mechanical/molecular mechanical approaches: from structure to activity.

An overview of the combined quantum mechanical/molecular mechanical (QM/MM) approach and its application to studies of biotransformation enzymes and drug metabolism is given. Theoretical methods to simulate enzymatic reactions have rapidly developed during the last decade. In particular, QM/MM methods provide detailed insights into enzyme catalyzed reactions, which can be extremely valuable in complementing experimental research. QM/MM methods allow the reacting groups in the active site of an enzyme to be studied at a quantum mechanical level, while the surrounding protein and solvent is included at a classical (and computationally less expensive) molecular mechanical level. Existing QM/MM implementations vary in the level of interaction between the QM and MM regions and in the way the partitioning into QM and MM regions is setup. Some general considerations concerning reaction modeling are discussed and a number of QM/MM studies related to drug metabolism are described. These studies illustrate that theoretical modeling of important metabolic reactions provides detailed insights into mechanisms of reaction and specific catalytic effects of enzyme residues as well as explaining variation in rates of conversion of different metabolites. Such information is essential in the development of methods to predict metabolism of drugs and to understand metabolic effects of genetic polymorphism in biotransformation enzymes.