Comparative QSAR analyses

Comparative QSAR analysis of derivatives of heterocycles as nonsteroid ligands of estrogen receptors 99CRV723. 

Gao H, Katzenellenbogen JA, Garg R, Flansch C. Comparative QSAR Analysis of estrogen receptor hgands. Chem Rev 1999 99 723-44. 

Comparative QSAR analysis of 5a-reductase inhibitors (azasteroids as inhibitors) 00CRV909. 

Guaianohdes have also been intensively examined toward protozoa like members of the genera Trypanosoma (sleeping sickness), Leishmania (leishmaniasis), and Plasmodium (malaria) only studies that also tested cytotoxic activity are considered here. In all cases, an antiprotozoal activity correlates positively with cytotoxicity, and the major determinants for activity are a,p-unsaturated carbonyl residues. Certain compounds are considerably more toxic against protozoa than against mammalian cells and vice versa. A comparative QSAR analysis has been undertaken, and both activities were found to depend mainly on the same structural elements and molecular properties. The observed variance in the biological data can maybe be explained by the positioning of the various molecules in the active site [63-65]. 

Comparative QSAR is a field currently under development by several groups. Large databases of known QSAR and 3D QSAR results have been compiled. Such a database can be used for more than simply obtaining literature citations. The analysis of multiple results for the same or similar systems can yield a general understanding of the related chemistry as well as providing a good comparison of techniques. 

Finally, very recently Pallavicini et al., in continuation of a previous study on ortho-monosubstituted compounds, designed and synthesized a series of 2-[(2-phenox-yethyl) aminomethyl]-l,4-benzodioxanes ortho-disubstituted at the phenoxy moiety [99]. The disubstituted analogues were tested for their binding affinities at the three oq-AR subtypes and for the 5-HT1A-R. The affinity values of the new compounds were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analogue, the well-known oq-AR antagonist WB-4101 (Scheme 8.1), and of the ortho-monosubstituted derivatives. The results suggested some distinctive aspects in the interaction of the phenoxy moiety of monosubstituted and disubstituted compounds with the cqa-AR and the 5-HTiA receptors. A classical (Hansch) QSAR analysis was applied to the whole... 

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. 

Summary of the 3D-QSAR Analysis Results for the 49 HIV-1 Protease Inhibitors Using the 3D-LogP Descriptor and Statistical Comparison with the Comparative Binding Energy Analysis (50) (COMBINE)... 

Based on their chemical structure, the organic chemicals were divided into a number of categories alkanes, alkenes, amines, aromatic hydrocarbons, benzenes, carboxylic acids, halides, phenols, and sulfonic acid. Linear regression analysis has been applied using the method of least-squares fit. Each correlation required at least three datapoints, and the parameters chosen were important to ensure comparable experimental conditions. Most vital parameters in normalizing oxidation rate constants for QSAR analysis are the overall liquid volume used in the treatment system, the source of UV light, reactor type, specific data on substrate concentration, temperature, and pH of the solution during the experiment. 

Previously, inductive QSAR descriptors have been successfully applied to a number of molecular modeling studies, including quantification of antibacterial activity of organic compounds (89), calculation of partial charges in small molecules and proteins (81), and in comparative docking analysis as well as in in silico lead discovery (82). Inductive QSAR descriptors have been used... 

Karakoc, E., Sahinalp, S.C., and Cherkasov, A. (2006) Comparative QSAR- and fragments distribution analysis of drugs, druglikes, metabolic substances, and antimicrobial compounds. J. Chem. Inf. Model. 46,2167-2182. 

The most commonly used and possibly even classical method of 3D QSAR analysis is the Comparative Molecular Field Analysis (CoMFA) technique introduced by R. Cramer et al. in 1988. In almost 20 years since, it has seen substantial development and enhancement, as well as the creation of several related approaches. In general terms, it aims to identify the spatial regions around the molecule where certain local properties have a positive or negative effect on activity. 

It has been shown that the more independent variables are involved in MLR QSAR analysis, the higher the probability of a chance correlation between predicted and observed activities, even if only a small portion of variables is included in the final QSAR equation (16). This conclusion is true not only for MLR QSAR, but also for any QSAR approach when the number of variables (descriptors) is comparable to or higher than the number of compounds in a data set. Thus, model validation is one of the most important aspects of QSAR analysis. 

Compadre, R.L.L., Byrd, C. and Compadre, C.M. (1998). Comparative QSAR and 3-D-QSAR Analysis of the Mutagenicity of Nitroaromatic Compounds. In Comparative QSAR (Devillers, J., ed.), Taylor Francis, Washington (DC), pp. 111-136. [R]... 

Lien, E.J. and Gao, H. (1995). QSAR Analysis of Skin Permeability of Various Drugs in Man as Compared to in Vivo and in Vitro Studies in Rodents. Pharm.Res., 12,583-587. 

Compadre RL, Byrd C, Compadre CM. Comparative QSAR and 3-D-QSAR analysis of the mutagenicity of nitroaromatic compounds. Comparative QSAR 1998 lll-36. 

Comparative Molecular Similarity Indices Analysis grid-based QSAR techniques > Comparative Molecular Surface Analysis grid-based QSAR techniques > Comparative Receptor Surface Analysis = CoRSA > Comparative Spectral Analysis spectra descriptors... 

Comparative QSAR and fragments distribution analysis of drugs, druglikes, metabolic substances, and antimicrobial compounds. 

Reddy, K.N., Dayan, E.E. and Duke, S.O. (1998) QSAR analysis of protoporphyrinogen oxidase inhibitors, in Comparative QSAR (ed. J. Devillers), Taylor Erands, Washington, DC, pp. 197-233. 

Zhang L, Gao H, Hansch C, Selassie CD. Molecular orbital parameters and comparative QSAR in the analysis of phenol toxicity to leukemia cells. J Chem Soc Perkin Trans 1998 2 2553-2556. 

H. Morita, A. Gonda, Lan Wei, K. Takeya, and H. Itokawa, 3D QSAR Analysis of Taxoids from Taxus cuspidata sr. nana by Comparative Molecular Field Approach , Bioorg. Med Chem. Lett, 1997, 7 (18), 2387 - 2392. 

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