Molecular Field Analysis CoMFA

introduced in 1988, assumes that a suitable sampling of the steric and electrostatic field around a set of aligned compounds might provide all the information necessary for understanding their biological properties, CoMFA came from earlier qualitative and quantitative lattice-based approaches to 3D-QSAR. 

CoMFA is attractive because of its combination of understandable molecular description, statistical analysis, and graphic display of results in a computer program that is unambiguous in its application. Molecules are described with molecular interaction fields similar to those computed by GRID, statistics are computed by and cross-validation, and 

In the first step, the aligned molecules are surrounded by a 3D lattice of regularly spaced points. The distance between neighboring points, the resolution level of the parameterization, is generally 1-2 A. The walls of the lattice extend at least 4 A beyond the union volume of the superimposed structures. For molecules the size of drugs, these settings lead to at least hundreds of grid points. 

In the next step, the user selects one or more probes, such as CH3, CH3 (the default), H+, or H2O, that will be used to calculate probe-ligand interaction energies at each lattice point. All the energies associated with a particular probe-ligand pair constitute a molecular field. Probes are chosen to describe the enthalpic noncovalent forces important for binding. For example, the CHj, H+, and H2O probes describe the steric, electrostatic, and hydrogen bonding properties of molecules. 

Because a typical CoMFA lattice contains at least a thousand grid points, if we want to calculate two types of field for 20 compounds, the total number of interaction energies exceeds 40,000. This large number of calculations is currently feasible only when potential energy functions are used. Typically Lennard-Jones (6-12) steric and Coulombic electrostatic fields, and sometimes hydrogen bond potential functions,are used. 

Braios, Calcul de.s Fonctions d Onde Moleculaire.s . Centre National de la Recherche Scientifique Paris. 1958. pp. 287-301. 

Rivail, Proceedings of the ACS Symposium - Methods and Applications of Hybrid Quantum and Molecular Mechanical Potentials , Las Vegas, Sept. 8-11, 1997, to be published. 

Ruedenberg, Localized Self-Consistent Orbitals in Atoms and Molecules , ed. O. Sinanoglu, Modem Quantum Chemistry Parti , Academic Press, New York, 1965, pp. 85-100. 

Eisenberg and W. Kauzman, The Structure and Properties of Water , Oxford University, New York, 1972 G. E. Walrafen, Water, A Comprehensive Treatise , ed. F. Franks, Plenum, New York, 1972. 

Martins-Costa, C. Millot, I. Tundn, M. F. Ruiz-Ldpez, and J. L. Rivail, J. Chem. Phys., 1997, 106, 

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Before the comparative molecular field analysis (CoMFA), BCUT descriptors, 4D-QSAR, and HYBOT descriptors arc discussed in more detail, some further descriptors are listed briefly. 

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. 

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. 

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. 

Bis(oxazohnes) figands have been so widely used for the Diels-Alder reaction between N-2-alkenoyl-l,3-oxazolidine-2-one and cyclopentadiene that Lipkowitz and Pradhan developed a QSAR (quantitative structure-activity relationship) using Comparative Molecular Field Analysis (CoMFA) for a set of 23 copper-catalysts containing mainly bis(oxazoline) figands. The generated... 

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... 

Partial Least Squares (PLS) regression (Section 35.7) is one of the more recent advances in QSAR which has led to the now widely accepted method of Comparative Molecular Field Analysis (CoMFA). This method makes use of local physicochemical properties such as charge, potential and steric fields that can be determined on a three-dimensional grid that is laid over the chemical stmctures. The determination of steric conformation, by means of X-ray crystallography or NMR spectroscopy, and the quantum mechanical calculation of charge and potential fields are now performed routinely on medium-sized molecules [10]. Modem optimization and prediction techniques such as neural networks (Chapter 44) also have found their way into QSAR. 

J. W. McFarland, Comparative Molecular Field Analysis (CoMFA) of anticoccidial triazines. J. Med. Chem., 35 (1992) 2543-2550. 

From comparative molecular field analysis (COMFA)5. This method can be used for electrical, steric and polarizability parameters. 

From comparative molecular field analysis (COMFA). 

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 >. 

Comparative Molecular Field Analysis (CoMFA), 6 16 16 755-757 pharmacophore generation and validation, 6 12 Comparative Molecular Shape Indexes Analysis (CoMSIA), J0 327t,... 

Cramer hi, R.D., Patterson, D.E., Bunge, J.D. Recent advances in comparative molecular field analysis (CoMFA). Prog. Clin. Biol. Res. 1989, 291, 161-165. 

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