Hypothesis Models

For QSAR model building purposes, the Cox2 inhibitor set was split into a learning set (LS, 80% of compounds) and a Validation set (VS, 20%). Splitting was done so as to ensure an equivalent relative distribution of actives and inactives throughout both sets, and ignoring the original provenience of the compounds. These sets were used to train and validate two types of linear QSAR approaches  

Each of these two QSAR model searches led to pools of several thousands of statistically valid linear equations, expressing the estimate of the Cox2 pICso value as linear combinations of molecular descriptors selected by a Genetic Algorithm (GA) [57, 

The linear models within each pool were subjected to a diversity analysis procedure in order to discard redundant equations based on roughly similar descriptor choices. 

This procedure assessed whether some of the different descriptors used by different equations were intercorrelated and, therefore, interchangeable [59]. The remaining diverse QSAR equations were further classified by size (number of descriptors they include). The best equations of each encountered size were kept for final validation with the VS molecules and for further analysis. Consensus models featuring average predictions over these equations were also generated and validated. We focus here on the discussion of the minimalist overlay-independent and overlay-based QSAR models, each including only six descriptors, and refer to the optimal consensus model of the overlay-based QSAR approach families for comparative purposes. 

Unfortunately, FfipFfop and HypoGen cannot process the large training sets of the size used for QSAR model building. The set of 29 most potent Cox2 inhibitors has been submitted to HipHop and the best of the resulting hypotheses has been qualitatively compared to the overlay-based QSAR model hypothesis. 

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Hypothesis Models and Similarity Models About Stmctural Reasons of Activity 131... 

Do Hypothesis Models Actually Tell Us More Than Similarity Models About the Structural Reasons of Activity. ... 

However, hypothesis models did clearly outperform similarity-based scoring with respect to the entire set. This advantage does not, as previously shown, stem from a better prediction of the subtle differences between the actives and inactives within the pharmacophoric Activity Zone . It may be ascribed to the ability of hypothesis models to correctly recognize actives that hide the key elements asked for by the model within a globally different pharmacophore pattern, which prevents them from being top ranked by the similarity search. 

Why Did Hypothesis Models Fail to Unveil the Key Cox2 Site-Ligand Interactions. ... 

Furthermore, there are many unanswered questions regarding idiosyncratic drug toxicity mediated by immune mechanisms, and the above explanations are not always sufficient. Some cases do not fit into the classical hapten hypothesis model. For example, antidrug antibodies are not always detectable. Immune reactions can take a period of months or even years to develop (e.g., hydralazine see below). 

Fig. 6. Hypothesis model representing the switching off and on of the FMR1 gene in X-fragile syndrome as a function of DNA structural dynamics...

Formation by precipitation from the hot gaseous silicate atmosphere escaped from the Earth, as proposed by Ringwood 30), may be considered a variant of the common fission hypothesis (Model a). Fission can be excluded because of the arguments presented in Chap. VII. There are a number of severe constraints that are difficult to overcome in both the precipitation hypothesis and the twin-planet model. 

The existence of clathrate-like water structure adjacent to the hydrophobic surfaces of macromolecules is an attractive hypothesis. Models have been proposed which have received some support from thermodynamical arguments [808]. However, this concept has proved ineffective as a basis for the interpretation of the structure associated with the many electron density solvent peaks, separated by 2.8 A to 3.0 A, which are frequently observed on the Fourier X-ray maps close to the surface of a protein [809, 810], Recently, however, some local clathrate-like water has been observed in special cases in the high-resolution studies of the small plant protein, crambin [811], in a hydrated deoxydinucleoside-phosphate drug complex [812], in (Phe4Val6) antamanide hydrate [8131 and in an oligodeoxy-nucleotide duplex [814],... 

The clinical protocol which includes the data acquisiton portion of a study must be designed with some expectation of the results these results are used to shape the protocol further. The hypothesis/model that was used as the analysis portion of this study was used to simulate the experimental measurements and to design the initial studies. Analysis of results was done by referring to this model. The results were used to modify the protocol for the second studies. The model is discussed below in the data analysis section. 

The diagrammed investigation begins with a hypothesis (model), which might come from inspiration or from an analysis of existing information. To test this hypothesis, the investigator designs some experiments, performs... 

The second hypothesis (Model 2) gives more weight to the transalkylation (reaction 5 of scheme 2), by assuming that only the moles of P exceeding... 

Despite the missing spectroscopic characterization of Fe(II) surface precipitates in such systems, analysis of adsorption isotherms of ferrous iron on several iron oxides (24) supports this hypothesis. Modeling of Fe(II) adsorption isotherms considering surface precipitation reactions (39) gave excellent fits to adsorption data (Figure 9). The model used allows for a transition from surface complexation to surface precipitation, which becomes relevant at surface saturations exceeding 20% (26). Fitted surface site density data of the studied iron oxides (Table I) agree with experimental data. Furthermore, the solubility product fitted for a hypothetical Fe(OH)2(s)... 

S.H. Kim, S3nnmetry Recognition hypothesis model for tRNA binding... 

Figure 2 The use of a 3D hypothesis model to focus a virtual library on compounds possessing the activity pattern. Through the use of generalized chemical features, diverse compounds are chosen from which a library subset can be selected. The hypothesis shown is for famesyl protein transferase...

The way in which a hypothesis model can be used to focus a virtual library is depicted in Figure 4. The basic idea is to use how well a compound can achieve a specified binding... 

Figure 5 Focusing of theoretical library by a four-featured hypothesis model for HIV-RT antagonism at the 33% (top) and 16% (bottom) threshold levels, and using rigid (left) and minimized (right) fits...

Scheme 1 Two possible sources of systematic error in the calculation of a compound s fit to a hypothesis model...

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