5.2 Conformers and Charges

After a suitable set of fragments has been collected, the next step is to generate partial charges for each fragment. The final step is to generate conformers for the fragments. If no partial charges are added, MMFF charges will be generated by Brood each time it is executed.

Partial charges can be added using the molcharge program from QuacPac.

This section assumes that conformers will be generated with the OpenEye program Omega. If some other conformer generation program will be used, the procedure here must be adapted for use with the other program. Unfortunately, OpenEye is not able to provide support for other conformer generation programs.

One might expect the fragment file could simply be run through Omega in a normal way to generate a multi-conformer fragment file. Unfortunately, MMFF, as implemented inside the current version of Omega is not able to correctly handle attachment atoms.

To work around this, we mark the attachment atoms and convert them to methyl groups, then run Omega. The program dbhelper is used before running Omega to carry out these transformations. In order to facilitate attachment-atom marking, the .oeb or .oeb.gz file format is required.

dbhelper has only two command line arguments. These are (in order), the input file and the output file. dbhelper is used before running Omega.

The following shows an example useage of dbhelper.

prompt> dbhelper input.smi preomega.oeb.gz
prompt> molcharge -mmff preomega.oeb.gz preomega.crg.oeb.gz
prompt> omega2 -in preomega.crg.oeb.gz -out frag.db.oeb.gz -fraglib
fraglib.oeb.gz

In this example, input.smi is a file of molecular fragments with attachment atoms (such as those produced by Chomp). The file preomega.oeb has the same fragments but with the attachment atoms marked and converted to methyl groups. preomega.crg.oeb.gz contains the same methylated fragments with MMFF partial charges. Finally, frag.db.oeb.gz is a 3D multi-conformer file of all the fragments with marked methyl groups. In this example, it is critical that the files preomega.oeb.gz, preomega.crg.oeb.gz and frag.db.oeb.gz are in .oeb or .oeb.gz format in order to keep track of the attachment-point atoms.

We realize this is a three-step process that could be replaced by a single step. In future releases of Omega and molcharge, we hope to include the ability to process attachment atoms directly.

				Brood: Fragment replacement for Medicinal Chemistry

				Brood: Fragment replacement for Medicinal Chemistry