Pharmacophoric Model Interpretation

The first part of this section describes how this interpretation is done and which assumptions have been made to retrieve plausible results. The second part will then describe the algorithms used to compute bond characteristics from geometric information, because the PDB file format and its successors include no means to specify hybridization states or bond orders, which are essential for the characterization of properties of small organic ligands. Ligand bond characteristics interpretation is a prerequisite for the step to follow the detailed description of protein-ligand interactions by pharmacophore models. 

As a second prerequisite, a valid pharmacophore model has to provide insight into the structure-activity relationships (SARs) or at least explain them. At this stage, the question is, Can the hypothesis interpret a SAR Such analysis will judge without appeal a poor dataset or an over-simplistic pharmacophore searching method. 

Lloyd, G. G., Garcia-Sosa, A., Alberts, I. L., Todorov, N. P., andMancera, R. L. (2004) The effect of tightly bound water molecules on the structural interpretation of ligand-derived pharmacophore models. J. Comput. Aided Mol. Des. 18, 89-100. 

The interpretation of the results obtained in this parallel screening study is straightforward. Visualization of hits (true ones and false positives) in a heat map (Figure 10.2) where the pharmacophore models are represented in columns and the ligands in rows green boxes indicate correct retrieval of a compound by a model for the correct target, while red... 

As we have seen, molecular descriptors constitute information about steric and electronic constraints conferred by chemical structure [104, 105]. Molecular descriptors underlie both pharmacophore models [106, 107] and analyses of similarity or diversity among compound collections [108,109]. The calculation of descriptors therefore serves as a starting point in the analyses of small-molecule relationships assessed prior to compound synthesis, before selecting compounds for HTS, and in the interpretation of biological measurements of small-molecule perturbation. 

Why should Gox2 activity be at all related to the presence or absence of certain pharmacophore feature pairs in a molecule Certainly, it can be argued - using the typical interpretation given to QSAR models based on autocorrelogram-type descriptors [63] - that the selected pharmacophore feature pairs stand for pairs of functional groups that are involved in direct interactions with the site, and these functional groups must be found at a fixed relative distance. However, this model... 

The results of any QSAR model (not only GRIND generated models) express the correlation between the differences in the structure of the compounds and their differences in biological properties. Structural features which are common to every compound in the series are simply not considered in the analysis. Any pharmacophoric interpretation of the results of a QSAR analysis will miss structural features shared by all the compounds. This fact is not trivial, because most series are constituted mainly of compounds with a certain degree of affinity for the receptor and this reveals that most of them have relevant common features. Therefore, as stated previously, none of these features will be present in the results of the models and no pharmacophore derived from this analysis will incorporate them. Moreover, the QSAR model results also inform us of structural features that are detrimental for the activity, while the pharmacophores are often focused only on the structural features that are needed to obtain active compounds. 

For all the above reasons, the results of the QSAR models obtained with GRIND should not be considered as pharmacophores. A correct and sensible interpretation of these results would be extremely useful, but its over-interpretation can be misleading and produce unrealistic expectations. It should also be stressed that the above-mentioned considerations are applicable to most QSAR and 3D QSAR results and are not a problem strictly linked to GRIND. 

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