Craig plots

Another way to identify correlations is to plot the values of the parameters in graphical form this can help to identify any correlations and the presence of outliers. A Craig plot is a two-dimerrsional scatterplot of one parameter against another ideally, the molecules should sample from all four quadrants of the plot. 

Larger, more sterically demanding R-groups tend to also have a higher lipophilicity. Does this statement pose a challenge for a Craig plot of sterics versus lipophilicity Why or... 

Craig plots are two dimensional plots of one parameter against another (Figure 4.6). The plot is divided into four sections corresponding to the positive and negative values of the parameters. They are used, in conjunction with an already established Flansch equation for a series of related aromatic compounds, to select the aromatic substituents that are likely to produce highly active... 

Figure 4.6 An example of a Craig plot of para Hammett constants cr against para tt values. [Reprinted with permission of John Wiley and Sons, Inc. from Craig P N (1980). In Burgers Medicinal Chemistry (M E Wolff, Ed.) 4th ed., Part 1 p. 343. Wiley, New York. Copyright [1980 John Wiley and Sons Inc.]...

Structure building, manipulation. Energy minimization of organic, inorganic, and polymer units. Stick, ball-and-stick, or space-filling display. QSAR Craig plots. PC. 

Although tables of tt and a factors are readily available for a large range of substituents, it is often easier to visualize the relative properties of different substituents by considering a plot where they axis is the value of the or factor and the x axis is the value of the tt factor. Such a plot is known as a Craig plot. The example shown in Fig. 

The Craig plot is useful in planning which substituents should be used in a QSAR study. In order to derive the most accurate equation involving tt and a, analogues should be synthesized with substituents from each quadrant. For example, halide substituents are useful representatives of substituents with increased hydrophobicity... 

Craig plots can also be drawn up to compare other sets of physicochemical parameters, such as hydrophobicity and MR. 

It is also important to make enough structures to make the results statistically meaningful. As a rule of thumb, five structures should be made for every parameter studied. Typically, the initial QSAR study would involve the two parameters tt and a, and possibly Es. Craig plots could be used in order to choose suitable substituents. 

The right substituent choice minimahzes the number of test compounds that have to be synthesized to insnre a significant space volume. This point represents a 3D extension of the Craig plot discnssed by Craig" and by Anstel. In this context, the decision tree proposed by Topliss allows a fast identification of the snbstitnents associated with the highest potency. Application examples of the Topliss scheme are discussed by Martin and Dnnn. ... 

Various strategies have been advocated in order to cover the physicochemical parameter space of a series of new compounds as well as possible. Familiar strategies go back to proposals by Topliss and Craig. Both are schemes used for substituent variation at a selected site. The Topliss substitution scheme can be used to optimize aromatic and aliphatic substituents using a fixed set of substituents and rules. A Craig plot is a 2D plot of selected descriptors, for example, Hammett electronic properties) and Hansch 7T values (lipophilicity). Substituents can be selected from each quadrant of this plot such that they vary widely in their properties, for example, lipophilic and hydrophilic, electron-donor and electron-acceptor, and to ensure the two properties are not correlated in the selected set which is preferable for the generation of stable QSAR models. 

A further extension would be to consider a 3D Craig plot using three descriptors, for example, reflecting steric, lipophilic and electronic properties of the substituents. In that case, substituents may be chosen from the eight octants. If one wants to consider even more descriptors, this approach becomes impractical. In that case, more advanced experimental design techniques may be applied. One approach taken by Hansch and Leo was to use CA to define sets of aliphatic and aromatic substituents useful in the design of compounds for synthesis, such that various aspects of the substituents are taken into account in a balanced way. ... 

Hansch analysis tries to correlate biological activity with physico-chemical properties by linear and nonlinear regression analysis, finding property-activity relationship models. A Craig plot is a plot of two substituent parameters (e.g., Hansch-Fujita n and Hammett a values). The simplest Hansch analysis is based on the Hansch linear model [Kubinyi, 1988b], defined... 

Topliss tree and Craig plot Factorial, central composite and D-optimal designs Principal properties of substituents Drug-like properties Combinatorial libraries Virtual screens IV Determining relationships between chemical and biological data A Overview... 

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