CoMFA contour maps

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. 

CoMFA contour maps for the standard alignment database (n = 199, 2A/C.3). 

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.

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.)...

Fig. 3.11. CoMFA contour maps for arylpyrazole antagonists of cannabinoid receptor subtypes CB, (A) and CB2...

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...

Within the CoMFA electrostatic map, red contours are displayed in areas where negative charge is associated with increased activity of the database analogues. Red contours are visible near the peroxide bridge, supporting the important role the peroxide plays in activity and near 0-11 (or N-l 1). There are also red contours in... 

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. 

Greco, G., Novellino, E., Pellecchia, M., Silipo, C. and Vittoria, A. (1994a). Effects of Variable Sampling on CoMFA Coefficient Contour Maps. J.MoLGraphics, 12, 67-68. 

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). 

---