MetaSite7

Most drugs are metabolized by Cytochrome P450 enzymes, which are primarily found in the liver. These cytochromes, along with about thirty other enzymes, carry out biotransformations known as phase I reactions. Additionally, around twenty other enzymes are responsible for phase II reactions, which generally involve conjugation processes. While cytochromes are involved in most metabolic processes, there is growing interest in understanding the mechanisms of non-CYP metabolic reactions.

In MetaSite 7, there are 23 non-CYP phase I enzymes considered. Besides FMO3 and AOX1, which were already present in MetaSite 6, the list has been expanded to include eight families and their related isoforms. Furthermore, enzymes responsible for the main phase II conjugation reactions have also been added, covering 11 different families and 19 enzymes in total.

In addition to these new enzymes, the computational method used in MetaSite 7 is innovative. Predictions are based not only on the ligand’s reactivity-structure relationship but also heavily on a three-dimensional component. This component relies on the 3D structure of the enzyme and the ligand’s ability to interact with it, exposing the reactive group and facilitating the reaction mechanism.

MetaSite command-line execution is controlled through script files written in a simple declarative language, allowing for sequential command execution. This language provides flexibility similar to the graphical interface, enabling operations such as opening, saving, and manipulating MetaSite document files. Users can alternate between command-line and GUI execution, such as importing objects and performing calculations via the command line, then browsing results in the GUI. In MetaSite7, these options are expanded to include all non-CYP Phase I enzymes, Phase II enzymes, or a combined CYP -Phase I – Phase II process.