Comparative molecular potential analysis

The use of additional (or other) fields than the default steric and electronic fields of the original CoMFA method, together with PLS analysis or GOLPE, is quite common as a valuable extension of the CoMFA program, but it also constitutes an alternative to the relatively expensive commercial software. A combination of shape, lipophilic, steric, and electrostatic potentials in comparative analyses was termed comparative molecular potential analysis (CoMPA) [1014],... 

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. 

However, it is normally assumed that the conformers that bind to target sites will be those with a minimum potential energy. Since molecules may have large numbers of such metastable conformers a number of techniques, such as the Metropolis Monte Carlo method and comparative molecular field analysis (CoMFA), have been developed to determine the effect of conformational changes on the effectiveness of docking procedures. 

Molecules are characterized by potential hydrogen bonding, polar, hydrophobic, and electrostatic interactions in 3D space, using 3D molecular fields. Techniques such as Comparative Molecular Field Analysis (CoMFA), which considers the 3D distribution of electrostatic and steric fields, have been applied to congeneric series of enzyme substrates or inhibitors generating 3D QSAR equations. Most examples of such applications are to modeling CYP substrate and inhibitor specificity and these have been extensively reviewed in the literature (Ekins et al., 2000 2001 Ter Laak and Vermeulen, 2001 Ter Laak et al., 2002). 

Kim, K.H. (1993f). Use of the Hydrogen-Bond Potential Function in Comparative Molecular Field Analysis (CoMFA) An Extension of CoMFA. In Trends in QSAR and Molecular Modelling 92 (Wermuth, C.G., ed.), ESCQM, Leiden (The Netherlands), pp. 245-251. 

Kroemer, R.T., Hecht, P. and Liedl, K.R. (1996). Different Electrostatic Descriptors in Comparative Molecular Field Analysis A Comparison of Molecular Electrostatic and Coulomb Potentials. J. Comput. Chem., 17,1296-1308. 

Masuda, T., Nakamura, K., Jikihara, T., Kasuya, E, Igarashi, K., Fukui, M., Takagi, T. and Fuji-wara, H. (1996). 3D Quantitative Structure-Activity Relationships for Hydrophobic Interactions. Comparative Molecular Field Analysis (CoMFA) Including Molecular Lipophilicity Potentials as Applied to the Glycine Conjugation of Aromatic as well as Aliphatic Carboxylic Acids. Quant.Struct.-Act.Relat., 15,194-200. 

In addition to an extensive summary provided previously on this moiety (8), Brouillette et al. (209) employed comparative molecular field analysis (CoMFA), a three-dimensional structure-activity technique, to provide a new potential anticonvulsant, 2-hydroxy-2-phe-nylnonanamide (40), whose Na-i-channel inhibition (IC50 = 9 fiM) compared favorably to 40 yM for phenytoin (1). This study suggested that the hydantoin ring system is not necessary in Na+channel binding. Research on water-soluble prodrugs of phenytoin has continued since the work by Stella, which led to the synthesis of fosphenytoin (Id) (8,209-215). A... 

Carrupt P-A, Gaillard P, Billois F, Weber P, Testa B, Meyer C, et al. The molecular lipophilicity potential (MLP) A new tool for logP calculations and docking, and in comparative molecular field analysis (CoMFA). In Pliska V, Testa B, van de Waterbeemd H, editors, Lipophilicity in drug action and toxicology. Weinheim VCH, 1996. p. 195-217. 

Carrupt, P. A., Gaillard, R, Billois, E., Weber, R, Testa, B., Meyer, C., Perez, S. The molecular UpophiUcity potential (MLR) a new tool for logP calculation and docking, and in comparative molecular field analysis (CoMEA). In UpophiUcity in Drug Action and Toxicology (Pliska, V, Testa, B., van de Waterbeemd, H., Eds). Wiley-VCH Weinheim, 1995, pp. 195-215. 

Kim, K.H., Greco, G., Novellino, E., Silipo, C. and Vittoria, A. (1993) Use of the hydrogen bond potential function in a comparative molecular field analysis (CoMFA) on a set of benzodiazepines. 

Comparative molecular field analysis (CoMFA) including molecular lipophilicity potentials as applied to the glycine conjugation of aromatic as well as aliphatic carboxylic adds. Quant. Struct. Act. Relat., 15, 194-200. 

Further additions to the 3D-QSAR arsenal include comparative molecular similarity indices analysis (CoMSIA) [15], 4D-QSAR [16], COMPASS [17], receptor surface models [18], the pseudoreceptor approach [19], ComPharm [20], and comparative molecular surface analysis (CoMSA) [21], 3-D-invariant, alignment-free descriptor systems such as comparative molecular moment analysis (CoMMA) [22], EVA [23], WHIM [24], and ALMOND [25], have also become available. A survey of the 3D-QSAR literature reveals 1154 entries in the Chemical Abstracts Plus database of these, 79% are journal publications, 19% are conference proceedings, and four are patents related to, or using, 3D-QSAR models. As the number of potential targets amenable to drug discovery is increasing exponentially, it is likely that 3D-QSAR models and methodologies will continue to be developed in the next decade. 

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