- You will find the drop down in the menu bar, next to the definition entry (cp. part 1); choose whether you would like to , , , or a pharmacophore. Here we will concentrate on the definition of a new pharmacophore, as the other entries are even more straight-forward. (Note: you will only be able to define a pharmacophore after the receptor definition.)
- By clicking –> , the dialog opens. You will notice two tabs, and . Both can be combined by prioritizing them or choosing logical expressions (see below).
- : when choosing this tab you will notice 3 sub-fields in the field: ('h_acc', 'h_don'), ('amide', 'phenyl_center', 'phenyl_ring', 'ch3_phe'), and ('ch', 'ch2', 'ch3', 'aro', 'sulphur'). These are, in order of importance, the possible interactions that you can define on the receptor side, in order to influence the result of a particular docking, and by clicking on each entry it will be highlighted, and be displayed in the 3D viewer, ready to be selected. In the figure above you can see the hydrogen bond donors and acceptors ('h_don', 'h_acc') highlighted, and both types are displayed in the 3D viewer: white surfaces for hydrogen bond donors and red for acceptors.
- You choose the relevant interaction spheres by clicking on them. As a consequence, they will be labelled, and the same information will appear in the box below the box. (Hint: it may be easier to turn off the Binding site surface in the tree view before displaying the surfaces for pharmacophore definition). Here you have the following entries, from left to right:
- The eye
 turns a label on or off.
- The cross
 deletes a pharmacophore surface definition.
- The indicates a letter that can be used in the logical combination of interaction constraints.
- Under you can choose whether to define an interaction as 'essential' (must be fulfilled) or 'optional' (can be fulfilled).
- defines the type of pharmacophore interaction, in this case 'h_acc'.
- The defines the chain ID, the amino acid identifier and the residue number.
- defines the atom name, in this case '_OD1' and '_OD2'.
- The last entry, is the identifier for the surface and gives the opportunity to decide between two lobes of a surface, in this case between lobe '0' and '1' of the oxygen in a carboxylate group (in our example, lobe '1' is chosen for both oxygen atoms '_OD1' and '_OD2').
- At the bottom, in the box you can now use the ID of the corresponding entries above to logically combine them. Here we combined the two 'h_acc' and 'h_don' pharmacophore definitions in an exclusive way by type "A or B" which means that either of the two have to be fulfilled.
You can also set the by defining each entry as either 'essential' or 'optional', which later can be adjusted by giving the minimum and maximum number of optional constraints.
- When choosing the tab, you will be able to define the center of a sphere (by clicking initially on an atom), which can then be moved around by changing the , , coordinates, and which can be adjusted in size by changing the radius. The cool thing about the spatial constraint is that it can basically be loaded with any kind of feature that can be expressed by SMARTS.
- Underneath the box, you can define that have to be matched/must not be matched by the sphere:
- : choose an element of the ligand that has to be in that sphere after the docking is completed.
- : define any kind of SMARTS expression. You can also use recursive SMARTS ($). When your SMARTS expression is correct, it will be highlighted in green, if it is not, it will remain red. For a detailed introduction how to use SMARTS within FlexX, please refer to the user guide.
- : Here you can pick from a list of predefined SMARTS expressions, which will be used for your sphere, in our example, hydrophobic atoms.
- Clicking will list your definitions in the box below the box. In this case you have the following entries:
- The eye will label/unlabel a sphere.
- The cross will delete a spatial interaction.
- The indicates a letter that can be used in the logical combination of interaction constraints
- Under you can choose whether to define an interaction as 'essential' (must be fulfilled) or 'optional' (can be fulfilled)
- , , are the sphere's coordinates
- corresponds to the sphere's radius
- contains the corresponding atom/substructure that was defined above.
- You can of course also use spatial constraints for logical combination with interaction constraints.
- When you are done with your pharmacophore definition, give it a name ('Pharm (#)' by default) and click .
|
