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Substituents

Pharmacophore Descriptors for Sustituents

General remarks

Pharmacophore descriptors can be derived on a per substituent basis by making use of rooted topological pharmacophores. These are topological pharmacophores in which one agon (pharmacophoric unit), the root, is singled out. It corresponds to the point of attachment of the substituents. This leads on the one hand to new moments, on the other hand to restrictions in the superposition of pharmacophores in similarity calculations. The rest of these remarks is identical to the remarks in tutorial Descriptors for Pharmacophoric Properties
Pharmacophoric properties of molecules are described in Moloc mainly by topological pharmacophores (-> theory). From these, two types of descriptors have been derived: moment- and similarity- ones. This tutorial illustrates how to calculate them for the example of a set of substituted hydroxyquinolone compounds for which plasma protein binding data are known (J.Med.Chem.40,4053,1997). Files, containing the structures, hdrqn.sd, and the experimental data, hdrqn.lst, can be found in the moloc/dat directory.

Generation of Topological Moment Descriptors

Because the generation of substituent descriptors requires a beforehand definition of a carrying scaffold, this option is implemented only in interactive mode.
  1. Start Moloc with the parameter hdrqn.sd, Moloc hdrqn.sd.
  2. Go to the library submenu 'lib/d' (definition, descriptors etc. of a scaffold library).
  3. Define the scaffold (fragment) on one particular structure 'f':
  4. Locate the scaffold in the other structures (option 's'), the program confirms with:
    New entry set: frgmch1
    Found 59 structures containing the fragment
  5. By default, all structures participate in the following actions. If you want to restrict those to a subset, do so with option 'm', which presents a selector of the structures containing the fragment.
The only positions at which the substituens vary are C2, C4, and C8 (on structure hdrqn_59, which is favorably set as the only visible one). One can either perform a full descriptor generation by selecting all three positions, or just for a single position, e.g. C8, which carries the most divers set of substituents. The first option yields a full description of the varying parts of the set of molecules. It has the disadvantage of specifying all substituents at the same level of description (order of the moments). Selecting each substituent position separately offers the advantage of adjustment of the description level to the substituent diversity. This, at the cost of having to concatenate files for a full description. We just treat position 'C8':

Topological Similarity Descriptors

Generation of Files with Substituent Descriptors

The resulting table can now be used to calculate a (linear) model for any measured properties of the 59 compounds.
Moloc now throws you into a new menu 'subtpr'

Options in menu 'subtpr' regarding substituents

Option 'a' (define action) offers several possibilities to examine or act on substituents at a given position. For our example we illustrate two options: analyse, and evaluate. The latter, which includes ranking of substituents, requires coefficients of a linear model. The evaluate option only appears, when these coefficients have been entered into Moloc with option 'c' (read model coefficients).

Analyse the Similarity Matrix of a Substituent Set

Ranking of Substituents

Substituents can be ranked according to their effect in a given linear model at a particular position.
  1. Select 'c' (read model coefficients) and specify the coefficient file (consult the help of option 'c' for the required format).
  2. Select 's' (separate model substituents) to produce substituent libraries (see next section) for the purpose of demonstration. More realistically, you might want to provide your own substituent library.
  3. Entries are recognized as substituents, when they have a single explicit hydrogen atom attached at the atom which makes the bond to the scaffold (i.e. H symbolizes the fragment-atom of attachment). Such substituent sets must be generated beforehand and are best put into a library (generated in 'lib/g, lib/n' or upon reading a multi-entry file). Of course such libraries can still be read in at that place with option './g'.
  4. Click 'a' (define action) and select evaluate.
  5. Now select '3' (the position number) and specify your substituents (preferably library-wise) to obtain a sorted list of the these substituents together with their influence on the model.

Separating Substituents

Separating substituents from the model compounds can be achieved with menu option 's' (separate model substituents), (see point 2 of the previous section). The chopped off (different) substituents, new Moloc entries, are gathered into libraries (entry-sets) called 'sub_1', 'sub_2', .... The point of attachment is represented by an additional atom, the type of which can be chosen in menu option 't' (atom type for attachment). By default this is an explicit hydrogen, and this is the only choice recognized by Moloc in substituent ranking.