Structure-activity relationships mechanistic

Nanbo, A. and Nanbo, T. (2002) Mechanistic study on N-demethylation catalyzed with P450 by quantitative structure activity relationship using electronic properties of 4-substituted N,N-dimethylaniline. Quant. Struct.-Act. Relat. 21,613-616. 

D. W. (2005) Skin sensitization reaction mechanistic applicability domains for structure-activity relationships. Chemical Research in Toxicology, 18, 1420—1426. 

These controversial findings inspired numerous subsequent studies on the structure-activity relationship of catalytically active compounds. Very detailed mechanistic studies on the catecholase activity of a series of structurally related dicopper(II) complexes have also been published by Casella and co-workers [37-40], who have grouped together different mechanisms earlier proposed for the catecholase activity of dicopper(II) complexes, as shown in Scheme 5.2. 

R. Benigni, Structure-activity relationship studies of chemical mutagens and carcinogens Mechanistic investigations and prediction approaches. Chem. Rev. 105, 1767-1800 (2005)... 

A.K. Debnath et al., Mechanistic interpretation of the genotoxicity of nitrofurans (antibacterial agents) using quantitative structure-activity relationships and comparative molecular field analysis. J. Med. Chem. 36, 1007-1016 (1993)... 

Hermens, J., Prediction of environmental toxicity based on structure-activity relationships using mechanistic information, Sci. Total Environ, 171, 235-242, 1995. 

Lo HC, Leiva C, Buriez O, Kerr JB, Olmstead MM, Fish RH (2001) Bioorganometallic chemistry. 13. Regioselective reduction of NAD+ models, 1-benzylnicotinamide triflate and P-nicotinamide ribose-5 -methyl phosphate, with in situ generated [CpRh(Bpy)H]+ structure-activity relationships, kinetics, and mechanistic aspects in the formation of the 1,4-NADH derivatives. Inorg Chem 40 6705-6716... 

Both cell cultures and animal studies have shown that many of the naturally occurring mono-, sesqui-, di-, sester-, and meroterpenoids as well as retinoids possess potentially chemopreventive activities. Terpenoids are minor but ubiquitous components of our diet, and have the advantage of being non-toxic or relatively non-toxic to humans. More mechanistic-oriented basic research is needed to elucidate the mechanisms of action. Studies of derivatives of these naturally occurring terpenoids are also necessary to elucidate the structure-activity relationship and to guide the development of novel chemopreventive agents. 

Figure 3. Plot of the logarithm of experimentally determined rate constants (iccat, min ) against energy barriers calculated with a QM/MM method for hydroxylation of severalparahydroxybenzoate derivatives by the enzymepara-hydroxybenzoate hydroxylase (PHBH), showing a linear correlation (r=0.96) between the calculated and experimental results [49,50]. This correlation supports the proposed mechanistic scheme, and the identification of the hydroxylation step as rate-limiting within it. It also validates the QM/MM method for this application, and shows that QM/MM results can be predictive and will be useful in the development of quantitative structure-activity relationships (QSAR). (Adapted from ref. 49, with thanks to Dr. L. Ridder).

Debnath, A.K., Hansch, C., Kim, K.H. and Martin, Y.C. (1993). Mechanistic Interpretation of the Genotoxicity of Nitrofurans (Antibacterial Agents) Using Quantitative Structure-Activity Relationships and Comparative Molecular Field Analysis. J.Med.Chem.,36,1007-1016. 

Mermens, XL. (1995a). Prediction of Environmental Toxicity Based on Structure-Activity Relationships Using Mechanistic Information. Sci. Total Environ., 171,235-242. 

In studies of quantitative structure activity relationships (QSAR), the relative potencies of a series of drugs are subjected to analysis with the hope that biological potency will be described by a mathematical equation. QSAR is an actuarial or statistical method in which only objective data are used with no intrusion of models or mechanistic hypotheses. The equation that is obtained not only accounts for the relative potencies of the compounds, but from it are deduced predictions of the potencies of untested compounds if the equation is valid, the predictions are ineluctable. The method thus has the capacity of yielding new (structurally related) drugs with desired potency, perhaps drugs with enhanced selectivity or fewer side effects. 

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