Selection of the Conformation

Molecules exist as flexible objects in 3D space. Therefore, although many properties can be calculated and understood from the structure diagrams of molecules, it is possible that using 3D properties directly would provide more insight into structure-activity relationships. A complication here is that to calculate 3D properties one must decide which conformation of the molecules to use. If there are structurally diverse molecules in the dataset, then one must usually also decide how to align the various molecules. 

The points need not be on a lattice, such as is used in CoMFA. The CoMSIA method places the points inside the union surface of the superimposed molecules. The properties are not interaction energies, but rather the similarity of the molecular field of the ligand at a particular point with that of a probe atom. For this purpose steric, electrostatic, hydrophobic, and hydrogen bond acceptor and donor properties are considered. In the Compass method, probe atoms are placed along 162 equally spaced rays 2A from the union surface of the molecules in their initial superposition. The properties for analysis are the distance from the surface of the molecule to each of the probe atoms. 

For Catalyst and Phase,the descriptors are the degree to which each of the common 3D features are occupied, with a penalty for a less-than-optimal distance or angle to the feature. 

We generated a CoMFA fit of the erythromycin esters, adding the substituents to the crystal structure of the unsubstituted compound. Only steric fields were significant. Table 3.5 (below) summarizes the statistics. 

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