Preparing the Ligands for Field-Based QSAR

The first step is to prepare the ligands to use. The ligands you add must be fully prepared 3D structures that are properly aligned. The alignment should ideally include conformational variation as part of the alignment. No facility is provided in these panels for preparing the structures, or aligning the ligands.

Structure preparation can be done with LigPrep (see the LigPrep User Manual — Contents), and generation of conformers can be done with ConfGen or MacroModel (see MacroModel Conformational Searches).

If you were using the Develop Pharmacophore Model panel to develop a pharmacophore hypothesis and the ligands were exported from this panel, they should already be prealigned to the pharmacophore model. No further alignment should be needed.

For best results, the alignment should include conformational variation. There are several ways in which you can align a set of ligands. Some of them involve a conformational search and alignment of the best conformer. Others perform a simple alignment without a search, and you would have to run the conformational search first.

  • Use the Shape Screening panel. This panel aligns the molecules to a query molecule on the basis of the shape or atom-type weighted shape. The method involves alignment of the best conformers from a conformational search. See Shape Screening Panel for details.

  • Use the Ligand Alignment panel. This panel does a quick conformational search and aligns the best conformer of the second and subsequent ligands to the first, replacing the structure with this conformer. See Ligand Alignment Panel for details.

  • Use the Superposition panel to align the ligands. The best choice is probably to align by a SMARTS pattern for the ligand core. You will also have to select the conformers that have the best alignment. See Superposition Panel for details.

    For example, you could run a conformational search for each ligand separately and store the results in separate entry groups, align each group separately to a chosen structure (for example, a known active), sort the ligands in each group by RMSD, then choose the entry with the lowest RMSD from each group.

  • Align the ligands to a pharmacophore hypothesis, using the Develop Pharmacophore Model Panel. The hit file from this job contains the aligned ligands.

  • Use the Phase command-line tool pharm_align_mol to align ligands to a hypothesis.

Whichever method you use, you should ensure that you get only one output structure for each ligand, which should be the best-aligned conformer.