Pharmacophore interaction

Fig. 6. The spheres corresponding to positive interaction pharmacophore element (IPE) represent regions that will be beneficial to the QSAR model. The sphere corresponding to negative IPEs indicate the region(s) where the particular IPE will degrade the QSAR model.

The results of the 4D-QSAR case study are interesting and provide large amounts of data about the system of interest, and, unlike static 3D-QSAR methods (CoMFA and SOMFA), 4D-QSAR is able to provide the exact locations of statistically important interaction pharmacophore elements. The ability of this method to overcome the question of What conformation to use and predict the bioactive conformation is impressive and a major reason to use the software. Yet it is the ability to construct manifold models and examine several models for the same alignment that is the true benefit of this method. Add to the list the ability to determine the best alignment scheme (based on statistical and experimental results) and this method will provide more information than one could imagine. This abundance of information is key when troubleshooting results that are not in agreement with current beliefs. 

It is obvious even from the most simple theoretical considerations that only the initial steps of the interaction can be represented by the interaction pharmacophore approximation. 

Comparison of the molecular structures of LSD and SKF 10856 (Figures 6 and 7, respectively) shows that the C12-C13 double bond is missing in the latter. Because the similarity of the interaction pharmacophores of 5-HT and LSD is based on the effect of this bond on the electronic properties of LSD, the SKF compound should not resemble 5-HT in its reactivity characteristics. Rather, the resemblance should be with tryptamine. The experimental findings from binding experiments to the P2 fraction of homogenates from guinea pig cortex confirm this theoretical prediction The affinity of SKF 10856 for the LSD/5-HT receptor (Kd h. lyM) is 100 times lower than that of either LSD or 5-HT to their receptor (KD = 5nM) and is comparable to that of tryptamine (K -. lyM) ... 

Interaction Pharmacophore Elements 4D-Molecular Similarity Analysis... 

Then, the Main Distance-Dependent Matrix (MDDM), for each pair of Interaction Pharmacophore Elements (IPEs) is estimated. The IPEs are specific and independent groups representing molecule functionality (Table Numerical Entriesl). The seventh IPE type (HS) encodes information about the overall molecular shape since all the nonhydrogen atoms are considered. From the MDDM estimated for the HS-HS pair, a similarity measure with respect to the whole molecule is obtained. 

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