Binding CoMFA

After an alignment of a set of molecules known to bind to the same receptor a comparative molecular field analysis CoMFA) makes it possible to determine and visuahze molecular interaction regions involved in hgand-receptor binding [51]. Further on, statistical methods such as partial least squares regression PLS) are applied to search for a correlation between CoMFA descriptors and biological activity. The CoMFA descriptors have been one of the most widely used set of descriptors. However, their apex has been reached. 

Flexible 3D alignment of a set of ligands binding to the same target and/or CoMFA analysis allowing the perception of a pharmacophore for this target. 

Cramer R D III, D E Patterson and J D Bunce 1988, Comparative Molecular Field Analysis (CoMFA). Effect of Shape on Binding of Steroids to Carrier Proteins. Journal of the American Chemical Societ 110 5959-5967. 

The biggest limitation of the CoMFA method is the alignment step. The algorithm superimposes the portions of the inhibitors that are of similar stmcture, assuming that they bind with similar orientations in the active site of the enzyme, which is not necessarily the case. Also, because of a problem with alignment, a CoMFA may fail when a few molecules are very dissimilar from all others in the series. Like QSAR, CoMFA does not require a stmcture of the relevant biological receptor, but does require knowledge about a series of inhibitory compounds. 

RD Cramer III, DE Patterson, JD Bunce. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110 5959-5967, 1988. 

A widely used 3-D QSAR method that makes use of PLS is comparative molecular field analysis (CoMFA), in which a probe atom is used to calculate the steric and electronic fields at numerous points in a 3D lattice within which the molecules have been aligned. Poso et al. [56] used the technique to model the binding of coumarins to cytochrome P450 2A5, with similar results to those obtained by Bravi and Wikel [55]. Shi et al. [57] used it to model the estrogen receptor binding of a large diverse set of compounds, and Cavalli et al. [58] used it to develop a pharmacophore for hERG potassium... 

The same assumptions apply to CoMFA as to ordinary Hansch analysis. These are additivity of effects and the availability of structurally similar (congeneric) molecules. The method does not account for pharmacokinetic effects, such as distribution, elimination, transport and metabolization. A prospective drug may appear to bind well to the receptor or enzyme, but may not reach the target site due to undesirable pharmacokinetic properties [8]. 

To refine this model qualitatively, the binding of several of these compounds was subjected to a CoMFA (Comparative Molecular Field Analysis) [39], This program examines electrostatic and steric parameters... 

Diana GD, Kowalczyk P, Treasurywala AM, Oglesby RC, Pevear DC, Dutko FJ. CoMFA analysis of interactions of antipicornavirus compounds in the binding pocket of human rhinovirus-14. J Med Chem 1992 35 1002— 1008. 

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