Methodology CoMFA

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). 

Comparative molecular field analysis (CoMFA) is comprised of relating measurements of the electrostatic and steric fields around a template molecule to the molecule s biological activity. The CoMFA methodology is based on the assump-... 

In this review, we focus mainly on the classical CoMFA methodology, but also mention other, more recent, developments. 

Norinder, U. Recent Progress in CoMFA Methodology and Related Techniques. Perspect. Drug Discov. Des. 1998, 72, 15-39. 

Norinder, U. (1998). Recent Progress in CoMFA Methodology and Related Techniques. In 3D QSAR in Drug Design - Vol. 3 (Kubinyi, H., Folkers, G. and Martin, Y.C., eds.), Kluwer/ ESCOM, Dordrecht (The Netherlands), pp. 25-39. 

Norinder U. Recent progress in CoMFA methodology and related techniques. In Kubinyi H, Folkers G, Martin YC, eds. 3D QSAR in Drug Design. Vol. 3. Recent Advances. Dordrecht Kluwer/ESCOM, 1998 25-39. 

This is a simplification of the whole process a great deal of work has been involved in many of the steps listed above and debate, often quite vigorous, continues over a number of them. A review of progress in CoMFA methodology lists four main areas where advances have been made ... 

The CoMFA methodology was also used to describe nonlinear lipophilicity-activity relationships, c.g. the inhibitory activities of quaternary alkylbenzyl-dimethylammonium compounds vs. Clostridium welchii (eqs. 206—208) [1025], other antibacterial and hemolytic activities [1026, 1027], and toxic activities of alkanes in mice (eqs. 209-211) [1026] the results of classical QSAR studies (eqs. 206, 207, 209, and 210) [23, 440] were compared with the corresponding CoMFA results (eqs. 208 and 211) [1025-1027] only homologous series of compounds were investigated. 

Dick Cramer provided insight and inspirahon that led to my interest in 3D QSAR methodology ]40] and was the impetus (the precursor of CoMFA was a lattice model [41] developed by Cramer and Milne at SKF) behind the development of CoMFA (Comparative Molecular Field Analysis) by Tripos [42], The success of CoMFA in... 

The popularity of commercial programs such as Comparative Molecular Field Analysis (4,12) (CoMFA) and Catalyst (13) has limited both the evaluation and use of other QSAR methodologies. Often well-known issues associated with CoMFA and Catalyst have come to be viewed as shortcomings that simply are accepted as working limitations in a 3D-QSAR analysis. In this section we challenge this position and present 3D- and nD-QSAR methods that are able to overcome some of the issues associated with current mainstream 3D-QSAR application products. 

A survey on 3D-QSAR literature (Oprea 2004) reported more than 1100 entries in the Chemical Abstracts database on CoMFA, 3D-QSAR, and related keywords. For CoMFA alone, 586 publications between 1988 and 2001 demonstrate its wide distribution and applicability. As the number of potential targets in drug discovery is steadily increasing, it is likely that 3D-QSAR models and methodologies will continue to be developed in the future. Successful applications were not only reported to understand target related affinity but also for some ADME relevant targets... 

An inexperienced user or sometimes even an avid practitioner of QSAR could be easily con-fiased by the multitude of methodologies and naming conventions used in QSAR studies. Two-dimensional (2D) and three-dimensional (3D) QSAR, variable selection and artificial neural network methods, comparative molecular field analysis (CoMFA), and binary QSAR present examples of various terms that may appear to describe totally independent approaches, which cannot be even compared to each other. In fact, any QSAR method can be generally defined as the application of mathematical and statistical methods to the problem of finding empirical relationships (QSARmod-els)of the form, D . D ), where... 

Kelkar, M.A., Pednekar, D.V., Pimple, S.R. and Akamanchi, K.G. (2004) 3D QSAR studies of inhibitors of cholesterol ester transfer protein (CETP) by CoMFA. CoMSlA and GFA methodologies. Med. Chem. Res., 13, 590-604. 

Not all the above-mentioned studies fulfill the necessary statistical requirements, especially proper PLS component selection by cross-validation. The crucial influence of different CoMFA options on the obtained results has been demonstrated [38,1059]. More objective alignment procedures, additional fields (e.g. a better consideration of polarizability), and more efficient variable selection procedures are needed. In addition, further research is necessary to find out which of the different CoMFA options should be selected to obtain stable and reproducible results. Theoretical and practical aspects, methodology and applications, as well as some limitations of CoMFA and related approaches have recently been reviewed in a book on 3D QSAR methods [38],... 

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