Steroids CoMFA

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. 

Coats, E. A. (1998) The CoMFA steroids as a benchmark dataset for development of 3D QSAR methods. Perspect. Drug Discov. Design 12/14, 199-213. 

Cavalli, A., Greco, G., Novellino, E., and Recanatini, M. (2000) Linking CoMFA and protein homology models of enzyme-inhibitor interactions an application to non-steroidal aromatase inhibitors. Bioorg. Med. Chem. 8, 2771-2780. 

Comparative molecular Leld analysis (CoMFA) is another promising approach developed in recent years for QSAR study. CoMFA is a molecular modeling technique forthe determination of molecular stericand electrostatic force Lelds (Tripos, 1992). It has been successfully used in deriving molecular descriptors for prediction of the bioactivity of steroids (Cramer etal., 1988), molecular Lux through a polymer membrane (Liu and Matheson, 1994), and metabolism and cytochrome p450 enzyme activities (Long and V felker, 2003). 

The use of the Pathfinder descriptor for QSAR is exemplified here through application to two datasets taken from the literature (i) 31 steroids utilized in the original CoMFA study [3], since considered a benchmark for evaluating QSAR methods [4] (ii) 55 inhibitors of HIV-1 reverse transcriptase proposed by Chan and coworkers [5], interestingly this series could only be successfully correlated by means of a structure-based approach [6]. 

Comparative Molecular Field Analysis (CoMFA). 1. Effect of Shape on Binding of Steroids to Carrier Proteins. 

Simon and his coworkers have developed (426) a quantitative 3D-QSAR approach, the minimal steric (topologic) difference (MTD) approach. Oprea et al. (452) compared MTD and CoMFA on affinity of steroids for their binding proteins and found similar results. Snyder and colleagues (453) developed an automated method for pharmacophore extraction that can provide a clear-cut distinction between agonist and antagonist pharmacophores. Klopman (404,454) developed a procedure for the automatic detection of common molecular structural features present in a training set of compounds. This has been used to produce candidate pharmacophores for a set of antiulcer compounds (404). Extensions (454)of this approach allow differentiation between substructures responsible for activity and those that modulate the activity. 

Coats, E.A. (1998). TTie CoMFA Steroids as a Benchmark Dataset for Development of 3D QSAR Methods. In 3D QSAR in Drug Design - Vol. 3 (Kubinyi, H., Folkers, G. and Martin, Y.C., eds.), Kluwer/ESCOM, Dordrecht (The Netherlands), pp. 199-213. 

Oprea, T.I., Ciubotariu, D., Sulea, T. and Simon, Z. (1993). Comparison of the Minimal Steric Difference (MTD) and Comparative Molecular Field Analysis (CoMFA) Methods for Analysis of Binding of Steroids to Carrier Proteins. Quant.Struct.-Act.Relat., 12,21-26. 

As a logical consequence, these methods were introduced in QSAR analyses and a new discipline, 3D QSAR, was bom. The major breakthrough in this field was achieved by Cramer et al.f who in 1988 described the application of comparative molecular field analysis (CoMFA) for the evaluation of the binding properties of steroids to carrier proteins. This approach, for which interestingly a patent application was filed by Cramer and Wold, and assigned to the software company Tripos, was based primarily on the previous work of Wise et on a dynamic lattice-oriented molecular modeling system (DYLOMMS) dating... 

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