Receptor 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. 

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. 

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]. 

CoMFA has also been used by Shim and co-workers [279] to help understand the interaction between rimonabant (382) and the CBi receptor. 

No new calculations were specifically devoted to this heterocylic system since CHEC-II(1996) <1996CHEC-II(8)249>. However, modeling of bioactive compounds containing this heterocycle have been published as exemplified by the the use of the highly potent dopamine D4 receptor ligand FAUCI 13 as template for comparative molecular field analysis (CoMFA) of dopamine D4 receptor antagonists <2001JME1151 >. 

Lopez-Rodriguez, M.L., Rosado, M.L., Benhamu, B., Morcillo, M.J., Fernandez, E. and Schaper, K.-J. (1997) Synthesis and structure-activity relationships of a new model of arylpiperazines. 2. Three-dimensional quantitative structure-activity relationships of new hydantoin-phenylpiperazine derivatives with affinity for 5-HTIA and oq receptors. A comparison of CoMFA models. Journal of Medicinal Chemistry, 40, 1648-1656. 

CoMFA/ CoMSIA Studies on Peripherally Acting CB1 Receptor Antagonists as Anti-Obesity Agents... 

Li AH, Moro S, Melman N, Ji XD, Jacobson KA (1998) Structure-activity relationships and molecular modelling of 3, 5-diacyl-2, 4-dialkylpyridine derivatives as selective A, adenosine receptor antagonists. J Med Chem 41 3186-3201 Li AH, Moro S, Forsyth N, Melman N, Ji XD, Jacobson KA (1999) Synthesis, CoMFA analysis, and receptor docking of 3, 5-diacyl-2, 4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists. J Med Chem 42 706-721... 

HTia, 5HT2a, and -adrenergic receptor affinities of 4-aryl-2- 4-[4-(het)arylpiperazino]butyl -2,3-dihydro-lH-, -2,3,5,6,7,8-hexahydro-lH-and -trans-4H,4flH-perhydropyrido[l,2-c]pyrimidinel,3-diones 48 were analyzed by CoMFA methodology (06JGM353). 

To continue the comparison, Martin prepared an additional set of 12 analogues of 12.18 and determined their activity against the 5-HT2 receptor. Both Nelson s Hansch equation and Martin s CoMFA model were used to generate calculated activities of the 12 new compounds. The summary of the findings is shown in Table 12.8. 

Agarwal, A., Pearson, P. P., Taylor, E. W., Li, H. B., Dahlgren, T., Herslof, M., et al. Three-Dimensional Quantitative Structure-Activity Relationships of 5-HT Receptor Binding Data for Telrahydropyridinyl Derivatives A Comparison of the Hansch and CoMFA Methods../. Med. Chem. 1993,36, 4006-4014. 

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