The Latent Indicator Variable revisited

In the previous Crapshoot we introduced (and greatly enjoyed) ‘QSAR: dead or alive?’ with its warning of “... vast number of studies with sufficiently poor predictive qualities to underscore a growing shadow of doubt on an ever-darkening correlative landscape” and are seriously considering the opportunity to invest in small German start up company who specialise in the manufacture of stork cages. It would appear that we are “... entangled in a descriptor jungle, unsure of how many and what types to use” and we have been reminded of the tale of The Tar Baby on more than one occasion when reading papers on QSAR modeling. Except that there was never any briar patch.

We thought that it would be a good time to return to the Latent Indicator Variable and have created a couple of graphics which we hope that you’ll find pretty. We’ll discuss these in more detail in the following Crapshoot so we’ll just say a bit about what the graphics are supposed to represent and we’ll leave it to you to enjoy them. The plots in the figures are idealised situations and we just ‘sketched’ the lines of fit so if you were to digitise the pictures you’d find that these are not least squares fits.

Figure 1 shows potency (pIC50) for two series of compounds. The green compounds are a series of structural analogs that are more potent against a related enzyme and were identified by testing compounds from the other project. None of the green compounds showed any great potency against the enzyme of interest and in fact the activity against the related enzyme was a bit of a safety worry. The project chemists are actually synthesising compounds similar to those reported by a competitor since they are more potent against the enzyme of interest while showing less activity against the related enzyme with the safety issue. One the horizontal axis is a variable which is a linear combination of descriptors which has been found to predictive of pIC50 and we write it in shorthand using the summation symbol. You will encounter linear combinations of descriptors time and time again in QSAR studies and we’ll have something to say about them in a future Crapshoot



Figure 2 shows a plot of plasma protein binding against logP for some carboxylic acids (green) and some neutral compounds (blue). On the horizontal axis is logP which is the logarithm (to base 10) of the octanol-water partition coefficient. This quantity should not be confused with logD even though it is sometimes equivalent to it. Even the less observant amongst you will note that increasing logP tends to result in stronger binding to plasma protein and the more observant readers will see that the carboxylic acids bind more strongly than the neutral compounds.



So there you have it. Two graphical illustrations of the Latent Indicator Variable. We’ll continue on this theme in the next Crapshoot and we hope that those of you in countries where Easter is celebrated will enjoy the holiday.

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