Steric contour maps

Figure 13. CoMFA contour maps about (+)-artemisinin for the standard alignment database (n = 199, 2 A/C.3). In the steric contour map to the left, green contours indicate areas where steric bulk is predicted to increase antimalarial activity, while red contours indicate regions where steric bulk is predicted to decrease activity. The electrostatic contour map on the right displays yellow polyhedra where partial negative charge is correlated with antimalarial activity the blue polyhedra indicating a relationship between partial positive charge and activity.

In addition to the QSAR data, which resulted from this program, three-dimensional contour maps were generated for both steric and elec-... 

Fig. 5 Example of steric CoMFA contour map results using APO (2-amino-3H-phenoxazin-3-one) for visualization near green area greater toxicity is correlated with more bulky groups and near yellow area with the less bulky group. 

Figure 6.11 a Diels-Alder reaction of N-2-alkenoyl-l, 3-oxazolidin-2-one with cyclopentadiene. b alignment of all 23 bisoxazoline and phosphinoxazoline ligands used in the CoMFA study. Regions of space where steric bulk should enhance or decrease stereo-induction are plotted using iso-contour mapping. 

Moreover, a final 3D-QSAR model vahdation was done using a prospective study with an external test set. The 82 compounds from the data set were used in a lead optimization project. A CoMFA model gave an (cross validated) value of 0.698 for four relevant PLS components and a conventional of 0.938 were obtained for those 82 compounds. The steric descriptors contributed 54% to the total variance, whereas the electrostatic field explained 46%. The CoMSIA model led to an (cross vahdated) value of 0.660 for five PLS components and a conventional of 0.933. The contributions for steric, electrostatic, and hydrophobic fields were 25, 44, and 31%. As a result, it was proved that the basic S4-directed substituents should be replaced against more hydrophobic building blocks to improve pharmacokinetic properties. The structural and chemical interpretation of CoMFA and CoMSIA contour maps directly pointed to those regions in the Factor Xa binding site, where steric, electronic, or hydrophobic effects play a dominant role in ligand-receptor interactions. 

Fig. 3.11. CoMFA contour maps for arylpyrazole antagonists of cannabinoid receptor subtypes CBi (A) and CB2 (B). Sterically favored areas (contribution level, 80%) are shown in green. Sterically unfavored areas (contribution level, 20%) are shown in yellow, and positive-potential favored areas (contribution level, 80%) are shown in blue. Positive-potential unfavored areas (contribution level, 20%) are shown in red. Plots of the corresponding CoMFA-calculated and experimental values of binding affinity (given as pKj) of arylpyrazole compounds at CBi (AA) and CB2 (BB) receptor, respectively are shown as well. (Adapted with permission from Chen J, Flan X, Lan R, et al. 3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach. J Med Chem 2006 49 625-636 with permission.) (See black and white image.)...

Figure 60 Graphical presentation of the results of CoMFA analyses. Positive (left diagrams) and negative (right diagrams) steric (upper diagrams) and electrostatic (lower diagrams) interactions of steroids with the human corticosteroid-binding globulin are shown as contour maps (reproduced from Figures 4 — 7 of ref. [1010] with permission from ESCOM Science Publishers BV, Leiden, The Netherlands).

CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) not only derive a mathematical equation but also generate a contour map (e.g., steric or electrostatic fields) that should or should not be occupied by new compounds with optimized characteristics (Fig. 34.6). 

Fig. 11 Steric and electrostatic contour map for the dual-model showing the contributions from each model. A depicts the contributions made by the a-model and G depicts the contributions made by the y-model...

The reaction shell is for both PES s a slim parabolic curve and thus the potential energy at Rc Vc(Yc). rises steeply with y demonstrating the strong steric requirements of this reaction. Inspection of the few trajectories calculated for j=0 and j>0 and superimposed on the contour maps of Fig. 7 reveals now clearly the tight correlation between the shape of Pc(j Etr) anisotropy of the PES. 

The result of the analysis corresponds to a regression equation with thousands of coefficients. Most often it is presented as a set of contour maps. These contour maps show favorable and unfavorable steric regions around the molecules as well as favorable and unfavorable regions for electropositive or electronegative substituents in certain positions (Section 6). Predictions for the test set (the compounds not included in the analysis) and for other compounds can be made, either by a qualitative inspection of these contour maps or, in a quantitative manner, by calculating the fields of these molecules and by inserting the grid values into the PLS model (Section 6). 

As already discussed, the functions that are used in CoMFA studies create relatively hard fields (cf. Figure 6, Section 5). Especially the variables of the steric fields sometimes show only values close to zero (no atoms around) or at the cutoff value (inside the molecules). Correspondingly, contour maps are most often fragmented and difficult to interpret, especially if a variable selection procedure has been applied in the analysis. ... 

The steric contribution contour maps of CoMFA and CoMSIA are plotted in Figs. 7 2a and 7.3a, respectively. To aid visualization, the most herbicidally active compound IH-18 is displayed in the maps. The CoMSIA approach provided more contiguous contour diagrams, which allowed physicochemical properties relevant... 

Fig. 7.2 CoMFA contour maps displayed with compound IH-18 (green) and the key residues in the binding site of the PD He El. a Steric field distribution and b Electrostatic field distribution...

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