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Mining a Database of Topological Pharmacophores

General remarks

Moloc offers the possibility to generate databases of topological pharmacophores. These databases can be ranked against the pharmacophore description of lead structures by applying a similarity measure between pharmacophores. Since this similarity is based on relating pharmacophoric units (agons), the results of the database search can be displayed in appropriate orientation with respect to the lead structure. In the following the steps in such a search are described one by one.
Example files can be found in Moloc's dat directory:

Generation of the Lead Pharmacophore File (.tpr)

If the lead structure (3-d pharmacophore) was built within Moloc, it is advisable to also store it as a disk file 'lead.mab' (lead.php) to enable later comparison with the hit structures found in the database search.

Database Search and 3-d Structure Extraction

The program to calculate similarities between topological pharmacophores is called Mtprsml, and resides in the same directory (moloc/bin) as the Moloc executable. It takes one or two arguments, files of topological pharmacophores, and a couple of parameters to modify the course of the calculation. The usage of the program is described by calling it without any argument.
In our case a possible call would be: Mtprsml -t10 -b100 -n1 -o l1.sml base.tpr lead.tpr
with the following explanations: When the list of 100 top hits has been generated, it is possible to produce a structure file (.mab), provided the structures of the database are also available in a multi-structure file, called e.g. 'base.mab'. The program Mabxtr will extract the structures of the hits upon issuing the command:
Mabxtr l1.sml base.mab
This command will produce a file 'l1.mab' which contains the structures in the order in which they appear in the hit-list file l1.sml.

Superimposition of Hits onto Lead and Hit Examination

For a visual examination of the hits of the database search the following steps may be followed:

Build a Database of Topological Pharmacophores

The program Mtprgn is provided to generate a database of topological pharmacophores which consists simply as a .tpr file containing the entries of the database. As with most batch programs coming with Moloc, its usage is printed to the screen by issuing the command 'Mtprgn' without any arguments.

Input

Several input formats are possible:

Multi-Fragment Structures and Protonation

Databases often contain multi-fragment structures (e.g. salts). Since topological pharmacophores are single-fragment objects, a flag -l (-L) allows to remove all but the largest fragment before the actual transformation to a topological pharmacophore.
The structures (fragments) as extracted from a database (e.g. corporate) may not always be in the proper state of protonation. This may have severe consequences for the results of the topologiclal pharmacophore calculations, because donor- or acceptor strengths of H-binder agons depend critically on the state of protonation. The flags -p (-P) provide measures to influence the state of protonation. The flag -P requires additional software (pcalc)!

Output and Examples

The output is always a .tpr file. Its name is taken from the input file name unless otherwise specified by the flag -o.