Tools for Selecting a Proper Molecular Alignment

The bioactive conformation need not correspond to the global minimum energy conformer calculated in vacuum or to that experimentally detected in a solution or in a crystal.However one determines the conformations and alignments to use, it is easier to propose a plausible superposition of diverse compounds if there is at least one rigid, active compound in the data set. Both point-by-point and field-fitting methods are used for alignment.  

If the training set includes only congeners, one can generally superimpose them on their common backbone, aligning as much of each structure as possible. In such cases, the conformation chosen for the common substructure may not affect the statistical results. 

However, with structurally diverse molecules, point-by-point superposition is more complicated. The pharmacophore concept provides one approach to the identification of an alignment for a noncongeneric set. A pharmacophore is the three-dimensional arrangement of points that a compound must possess for it to show a particular biological property. The points may be 

Several computational methods can identify conformations that can be superimposed with a reasonable overlap of user-supplied pharmacophoric points in each molecule. In the active analog approach, several potent, structurally diverse ligands are submitted to a systematic conformational search while pharmacophore interpoint distances are recorded for each energetically allowed conformation. Intersection of the distance maps of these molecules identifies sets of conformations with common distances between the pharmacophoric points. 

Other commercial programs for finding suitable molecular alignments exist,44 [jyt cannot be reviewed because their algorithms are not yet published. 

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