Table 1 Terms used for Template system

2D and 3D: two-dimensional and three-dimensional

Bay 1 and Bay 2: Residues located lower left and right of CYP1A, CYP2C and CYP3A Templates

Bi-molecule and uni-molecule binding: Interactions on Template with Trigger- and Pro-metabolized molecules combination, and with single molecule

Cavity-1 and Cavity-2: Holes in the middle of CYP3A4 Template. The residues in the holes (Cavity-1 residue and Cavity-2 residue) are expected to participate in the IJK-Interaction and triggering. These residues appear on Template plane after ligand’s passage

Entrance: Routes for the entry of ligands

Facial-side movement: CYP1A2-mediated pushing at Ring C, to transfer substrates toward Site of oxidation

Fjord: A central space at where no substrate stays on CYP1A Template

Front-residue: A residue existing at facial side of Ring B of CYP3A Template

Futile-sitting: A phenomenon of lack of oxidations associated with rotatable and non-substituted phenyl group of ligands

Groove: A space for ligand sittings located beneath of Width-gauge of CYP3A and CYP2E1

IJK-Interaction: Interaction of ligands with Rings I, J and/or K region is expected to initiate facial-side movement of ligand on CYP3A Template

Left-end: The left-side border of CYP2C Template located between Entrance and Shelf

N-Atom impedance: Rejection of sitting of pyridyl or secondary amino nitrogen atom at Position 31 of Ring eC1 of human CYP1A2

Placement Type: There are seven distinct types of ligand sittings on CYP3A4 Template, termed Type-1 to Type-7. These are associated with the usage frequencies for the interaction

Preferred order: Occurrence order of the reaction determined by the placement on CYP1A Template

Pro-metabolized molecule: Substrates to be oxidized or reduced are termed as “pro-metabolized molecule” in the simulation experiment

Rear-residue: A residue sitting at rear-side of Position 30 of CYP3A7 Template

Right-side movement: Right-direction shift of ligands entered in Rings A and B to Bay-2 direction on CYP3A4 Template

Shelf: A plateau-like shape area between Position 29 and Left-end of CYP2C Template

Sideway: Ligand migration route in the right side of Center-Area, which corresponds to Rings E-eEc-eC2-eC10-eC5-eC9-eC8 on CYP1A1 Template

Simultaneous plural-point contact: Initial interactions of CYP2C ligands start with their simultaneous plural-parts contact to Rear-wall standing upright at rear end of Template

Site of oxidation: A confined space of enzymatic catalysis to interact with heme

Thick-area: An area of CYP1A2 Template on where flexible or bulky shapes of chemicals as well as PAHs interact

Thin-area: A flat-area of CYP1A2 where flat shapes of aromatic hydrocarbons stay

Trigger molecule: A molecule, which is not oxidized, acts for triggering the catalysis. Trigger molecules need to have an overlap with pro-metabolized molecules on Template

Trigger-site: A site which Trigger residue moves to hold ligands to initiate catalyses. For examples, Position 26 of CYP3A Template, Position 10–11 of CYP1A and Position 11 of CYP2E1 correspond to Trigger-site

Type-1, Type-2 and Type-3 placements on CYP1A1: Ligands hang on Bay 2 residue through sitting at Position 33 of Ring eC2 on Type-1 placement. Ligands contact with Bay-2 residue at Ring eEc and have a protruding part on Ring eEa on Type-2 placement. Ligands take bottom-flattened sittings contacting simultaneously with the side part to Bay 2 residue and with the flat part to Bottom-residue on Type-3 placement

Uni-molecule and bi-molecule binding: Placements on Template with single molecule and with Trigger and Pro-metabolized molecules, respectively

Width-gauge: A guide tool to verify allowable width for ligand accommodation around Template which was determined empirically