Pharmacophore plot

Pharmacophore plots are three-dimensional scatter diagrams that represent the three-point pharmacophores exhibited by a particular structure. The axes represent the distances between the three centers, and each point represents a distinct pharmacophore, labeled by a symbol that indicates the three centers, and color-coded according to whether it contains 1, 2, or 3 identical centers. A typical pharmacophore plot generated using Chemical Design s Chem-X suite is shown in Figure 6. 

Figure 6 Pharmacophore plot generated by Chemical Design s Chem-X software suite...

Fig. 5.3 Principal component plots in pharmacophoric and topological spaces. Rectangles schematically indicate the activity zones .

Fig. 11.5. Distribution plots of (a) molecular weight (MW), (b) number of rotatable bonds (NRot), (c) SlogP, (d) number of pharmacophore (ph4) triangles, and (e) number of rings for the whole library (VER ref), all hits (Class 1-3), Class 1 hits, and nonhits. With kind permission from Springer Science+Business Media Journal of Computer-Aided Molecular Design, 23, 2009,603, l-Jen Chen and Roderick E. Hubbard, Fig. 6.

Since in pharmacophore-based VS only a part of the database molecules matches the model and therefore obtains an alignment score, a limited number of Se and 1-Sp values can be calculated and plotted. Thus, a selective model would result in an ROC curve that starts at the origin and finishes before it reaches the upper right comer where all active and inactive molecules are scored. However, to simplify the explanation of the ROC curve method, we suggest that the model would retrieve and score all database molecules, either because all database molecules are very similar or because partial matching of model features is allowed. In this case, an ideal pharmacophore model will score all actives higher than inactive database molecules. 

FIGURE 11.5 (a) A series of DGATl inhibitors with a benzylamidothiadiazole scaffold sharing a cyclohexylacetic acid as common pharmacophore, (b) Analysis of compound 4 with MetaSite3 [99]. The proposed main metabolite is the aliphatic hydroxylation product at the SOM. The scores plot ranks the thiadiazole alpha position on top of aU substrate sites (blue bar). Most probable SOM are color coded in a structure diagram (blue circle). For color details, please see color plate section. 

Just like structural keys, pharmacophore keys can be readily extended to account for multiple conformations. Three-point pharmacophore keys also lend themselves to visualization in the form of a three-dimensional scatter plot (see Section 5.4). A number of people have followed up Sheridan s work, most notably the groups at Chemical Design, Rhone-Poulenc, and Abbott. ... 

As we mentioned before (Section 2.1.10), pharmacophore keys may be derived from a single conformation or an ensemble of conformations. Moreover, pharmacophore maps of more than one structure may be combined into a single plot, a technique that is particularly useful for visualizing and comparing the pharmacophoric diversity of combinatorial libraries. 

As is the case for structural keys, pharmacophore keys can be readily extended to account for multiple conformations. Additionally, because pharmacophores are two- and three-dimensional objects, they are able to capture information on molecular shape and chirality. Three-point pharmacophore keys also lend themselves well to visualization via three-dimensional scatter plots (see section Visualization without Dimensionality Reduction below). Sheridan s original work has been extended by a number of groups, most notably those at Chemical Design [27], Rhone-Poulenc [30], and Abbott [10]. Davies and Briant [31] have employed pharmacophore keys for similarity/diversity selection using an iterative procedure that takes into account the flexibility of the compounds and the amount of overlap between their respective keys (see section Boolean Logic). 

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