Linearity potency

The second application of the CFTI protocol is the evaluation of the free energy differences between four states of the linear form of the opioid peptide DPDPE in solution. Our primary result is the determination of the free energy differences between the representative stable structures j3c and Pe and the cyclic-like conformer Cyc of linear DPDPE in aqueous solution. These free energy differences, 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. The predicted low population of the cyclic-like structure, which is presumably the biologically active conformer, agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide. 

Schild analysis is a very powerful method to quantify the potency of a competitive antagonist and to test whether the blockade of response by a molecule is consistent with simple competitive antagonism. Devised by Arunlakshana and Schild (1959), it is based on the principle that the antagonist-induced dextral displacement of a dose-response curve is due to its potency (Keq value, affinity) and its concentration in the receptor compartment. Since the antagonism can be observed and the concentration of antagonist is known, the Keq (denoted KB for antagonist) can be calculated. Die relationship between antagonism and concentration must be log-linear with a unit slope to adhere to true competitive kinetics. 

Oncogenic Risk Calculations. On the basis of the expos ire analysis and potential oncogenic risk (oncogenic potency might be more descriptive), a risk analysis will be performed according to statistical methods like linear extrapolation (one-hit model) or multistage estimation (9.). 

As an illustration of PLS regression (PLSl) we reconsider the inhibitory potencies of oxidative phosphorylation of 11 doubly substituted salicylanilides [ 17] in Table 37.1. An extended Hansch model is defined by the linear free energy relation ... 

As for the modeling of in vitro and in vivo potencies and selectivities, some interesting models were obtained on a subset of representative ligands. In fact, the QSAR analysis of functional activities for this set of compounds, although numerically limited, yields successful correlations [97]. Among these linear correlations, the following equation constitutes a significant example ... 

Clive D. 1977. A linear relationship between tumorigenic potency in vivo and mutagenic potency at the heterozygous thymidine kinase (TK+/-) locus of L5178Y mouse lymphoma cell coupled with mammalian metabolism. Dev Toxicol Environ Sci 2 241-247. 

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